Journal Articles

Rapid CAR-T manufacturing with low-intensity priming enhances CAR-T cell fitness and limits inflammatory programming in a phase 1 study Featured  

(1) Yang Z (2) Li S (3) Wang L (4) Li Y (5) Xu H (6) Li Y (7) Liu L (8) Yuan Z (9) Zhang Y (10) Zhang L (11) Chen Y (12) Zhang Q (13) Shen J (14) Wang M (15) Zhu W (16) He X (17) Wang Y (18) Dong Y (19) Wang S (20) Qian C

Cell stem cell

Yang and Li et al. developed a 2-day protocol called PrimeCAR in which T cells were primed ex vivo with low-intensity soluble anti-CD3 in combination with IL-7 and IL-21. Compared to a longer conventional CAR T cell manufacturing protocol, PrimeCAR T cell manufacturing yielded less activated, less differentiated CAR T cell products that maintained strong cytotoxicity, while limiting inflammatory cytokine signaling and associated toxicities. PrimeCAR T cells showed promising results for maintaining efficacy while limiting toxicity in two phase 1 trials in patients with either B-ALL or B-NHL.

(1) Yang Z (2) Li S (3) Wang L (4) Li Y (5) Xu H (6) Li Y (7) Liu L (8) Yuan Z (9) Zhang Y (10) Zhang L (11) Chen Y (12) Zhang Q (13) Shen J (14) Wang M (15) Zhu W (16) He X (17) Wang Y (18) Dong Y (19) Wang S (20) Qian C

Cell stem cell

Yang and Li et al. developed a 2-day protocol called PrimeCAR in which T cells were primed ex vivo with low-intensity soluble anti-CD3 in combination with IL-7 and IL-21. Compared to a longer conventional CAR T cell manufacturing protocol, PrimeCAR T cell manufacturing yielded less activated, less differentiated CAR T cell products that maintained strong cytotoxicity, while limiting inflammatory cytokine signaling and associated toxicities. PrimeCAR T cells showed promising results for maintaining efficacy while limiting toxicity in two phase 1 trials in patients with either B-ALL or B-NHL.

ABSTRACT: Conventional chimeric antigen receptor (CAR)-T manufacturing requires prolonged ex vivo activation and expansion, which may compromise T cell fitness and promote inflammatory differentiation. Here, we developed PrimeCAR, a 2-day manufacturing strategy combining low-intensity anti-CD3 priming with IL-7 and IL-21. Compared with conventionally manufactured CAR-T cells, PrimeCAR products exhibited a distinct transcriptional state characterized by preserved stemness-associated programs and a PrimeCAR-enriched primed naive T cell (Tn)-like state. Following antigen stimulation, PrimeCAR cells preferentially engaged proliferative programs while limiting exhaustion-associated regulators and inflammatory mediators. Functionally, PrimeCAR cells demonstrated enhanced expansion, persistence, and durable antitumor activity in xenograft models. In investigator-initiated phase I studies of relapsed or refractory B cell acute lymphoblastic leukemia and B cell non-Hodgkin lymphoma, PrimeCAR showed encouraging clinical activity with a favorable safety profile. Together, these findings demonstrate that rapid manufacturing with controlled early T cell priming selectively restrains inflammatory programming while preserving CAR-T cell fitness, providing a practical strategy for improving CAR-T manufacturing and therapeutic performance.

Author Info: (1) Chongqing Key Laboratory of Gene and Cell Therapy, Chongqing 400039, China; Chongqing Precision Biotech Co., Ltd., Chongqing 400039, China. Electronic address: yangzhi@precisio

Author Info: (1) Chongqing Key Laboratory of Gene and Cell Therapy, Chongqing 400039, China; Chongqing Precision Biotech Co., Ltd., Chongqing 400039, China. Electronic address: yangzhi@precision-biotech.com. (2) 920th Hospital of Joint Logistics Support Force of People's Liberationsi Army of China, Kunming 650100, Yunnan, China. (3) Chongqing Key Laboratory of Gene and Cell Therapy, Chongqing 400039, China; Chongqing Precision Biotech Co., Ltd., Chongqing 400039, China. (4) Chongqing Key Laboratory of Gene and Cell Therapy, Chongqing 400039, China; Chongqing Precision Biotech Co., Ltd., Chongqing 400039, China. (5) Chongqing Key Laboratory of Gene and Cell Therapy, Chongqing 400039, China; Chongqing Precision Biotech Co., Ltd., Chongqing 400039, China. (6) 920th Hospital of Joint Logistics Support Force of People's Liberationsi Army of China, Kunming 650100, Yunnan, China. (7) 920th Hospital of Joint Logistics Support Force of People's Liberationsi Army of China, Kunming 650100, Yunnan, China. (8) 920th Hospital of Joint Logistics Support Force of People's Liberationsi Army of China, Kunming 650100, Yunnan, China. (9) Chongqing Key Laboratory of Gene and Cell Therapy, Chongqing 400039, China; Chongqing Precision Biotech Co., Ltd., Chongqing 400039, China. (10) 920th Hospital of Joint Logistics Support Force of People's Liberationsi Army of China, Kunming 650100, Yunnan, China. (11) 920th Hospital of Joint Logistics Support Force of People's Liberationsi Army of China, Kunming 650100, Yunnan, China. (12) Chongqing Key Laboratory of Gene and Cell Therapy, Chongqing 400039, China; Chongqing Precision Biotech Co., Ltd., Chongqing 400039, China. (13) Chongqing Key Laboratory of Gene and Cell Therapy, Chongqing 400039, China; Chongqing Precision Biotech Co., Ltd., Chongqing 400039, China. (14) Chongqing Key Laboratory of Gene and Cell Therapy, Chongqing 400039, China; Chongqing Precision Biotech Co., Ltd., Chongqing 400039, China. (15) Chongqing Key Laboratory of Gene and Cell Therapy, Chongqing 400039, China; Chongqing Precision Biotech Co., Ltd., Chongqing 400039, China. (16) Chongqing Key Laboratory of Gene and Cell Therapy, Chongqing 400039, China; Chongqing Precision Biotech Co., Ltd., Chongqing 400039, China. (17) 920th Hospital of Joint Logistics Support Force of People's Liberationsi Army of China, Kunming 650100, Yunnan, China. (18) 920th Hospital of Joint Logistics Support Force of People's Liberationsi Army of China, Kunming 650100, Yunnan, China. (19) 920th Hospital of Joint Logistics Support Force of People's Liberationsi Army of China, Kunming 650100, Yunnan, China. Electronic address: sanbin1011@163.com. (20) Chongqing Key Laboratory of Gene and Cell Therapy, Chongqing 400039, China; Chongqing Precision Biotech Co., Ltd., Chongqing 400039, China. Electronic address: cqian8634@gmail.com.

Citation: Cell Stem Cell 2026 Oct 13 Epub10/13/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42869018

Tags:

NKG2D overexpression potentiates CAR-T cells through costimulation by tumor NKG2D ligands Spotlight 

(1) Li J (2) Han L (3) Zhu Q (4) Liu N (5) Ma H (6) Wu Z (7) Wang Y (8) Lin X (9) Wei J (10) Han W

Cell reports. Medicine

Li, Han, and Zhu et al. observed that T cell activation increased NKG2D ligand (NKG2DL) expression, enabling T cell depletion by NK cells. Overexpressing (OE) full-length NKG2D in CAR T cells led to its colocalization with NKG2DL on the cell surface, reducing NKG2DL detection (by cis masking) and NK killing. NKG2D-OE also improved CAR T cell cytotoxicity by binding NKG2DL on tumor cells (in trans) and increasing CAR-T activation, memory phenotype, CAR-proximal signaling, and proliferative capacity, without affecting exhaustion. NKG2D-OE improved CAR-T efficacy in heme and solid tumor models, and boosted tumor infiltration.

Contributed by Alex Najibi

(1) Li J (2) Han L (3) Zhu Q (4) Liu N (5) Ma H (6) Wu Z (7) Wang Y (8) Lin X (9) Wei J (10) Han W

Cell reports. Medicine

Li, Han, and Zhu et al. observed that T cell activation increased NKG2D ligand (NKG2DL) expression, enabling T cell depletion by NK cells. Overexpressing (OE) full-length NKG2D in CAR T cells led to its colocalization with NKG2DL on the cell surface, reducing NKG2DL detection (by cis masking) and NK killing. NKG2D-OE also improved CAR T cell cytotoxicity by binding NKG2DL on tumor cells (in trans) and increasing CAR-T activation, memory phenotype, CAR-proximal signaling, and proliferative capacity, without affecting exhaustion. NKG2D-OE improved CAR-T efficacy in heme and solid tumor models, and boosted tumor infiltration.

Contributed by Alex Najibi

ABSTRACT: Chimeric antigen receptor (CAR)-T cell therapy has achieved remarkable success in hematologic malignancies, but durable efficacy remains limited by insufficient CAR-T cell persistence. Here, we show that activated CAR-T cells upregulate multiple NKG2D ligands (NKG2DLs), increasing their susceptibility to natural killer (NK) cell-mediated CAR-T cell cytotoxicity. To address this vulnerability, we engineer CAR-T cells to overexpress full-length NKG2D (CAR-NG). NKG2D overexpression reduces the surface accessibility of endogenous NKG2DLs without decreasing their total protein abundance. In parallel, engagement of tumor-expressed NKG2DLs in trans provides additional costimulatory signals, enhancing CAR-T cell activation and proliferation while attenuating exhaustion-associated phenotypes. In hematologic and solid tumor models, CAR-NG cells exhibit reduced susceptibility to NK-cell-mediated cytotoxicity, improved tumor control, increased in vivo expansion, deeper tumor infiltration, and no evident additional toxicity compared with conventional CAR-T cells. These findings identify NKG2D overexpression as an engineering strategy that enhances CAR-T antitumor activity primarily through tumor NKG2DL-dependent trans costimulation.

Author Info: (1) Department of Biotherapy, the First Medical Center, Chinese PLA General Hospital, Beijing, China. (2) Department of Biotherapy, the First Medical Center, Chinese PLA General Ho

Author Info: (1) Department of Biotherapy, the First Medical Center, Chinese PLA General Hospital, Beijing, China. (2) Department of Biotherapy, the First Medical Center, Chinese PLA General Hospital, Beijing, China. (3) Department of Biotherapy, the First Medical Center, Chinese PLA General Hospital, Beijing, China. (4) Department of Biotherapy, the First Medical Center, Chinese PLA General Hospital, Beijing, China. (5) Department of Biotherapy, the First Medical Center, Chinese PLA General Hospital, Beijing, China. (6) Department of Biotherapy, the First Medical Center, Chinese PLA General Hospital, Beijing, China. (7) Department of Biotherapy, the First Medical Center, Chinese PLA General Hospital, Beijing, China. (8) Beijing Changping Laboratory, Beijing, China; School of Basic Medical Sciences, Tsinghua University School of Medicine, Beijing, China; Tsinghua-Peking Center for Life Sciences, Beijing, China. Electronic address: linxin307@tsinghua.edu.cn. (9) Beijing Changping Laboratory, Beijing, China. Electronic address: woshiwjs@hotmail.com. (10) Department of Biotherapy, the First Medical Center, Chinese PLA General Hospital, Beijing, China. Electronic address: hanwdrsw@163.com.

Citation: Cell Rep Med 2026 Oct 16 103116 Epub10/16/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42887502

Tags:

Peripheral Blood as the Sole Source for Cancer Neoantigen and Reactive T-Cell Discovery Spotlight 

(1) Garcia-Garijo A (2) Creus-Gonz‡lez I (3) Levy PL (4) Moreno-C‡rdenas AB (5) Prieto-Fern‡ndez E (6) Lozano-Rabella M (7) Fajardo CA (8) Pujol-Borrell R (9) Mar’n-Bayo A (10) Kusnick J (11) Gonzalez J (12) Brujas C (13) Gartner JJ (14) Yuste-Estevanez A (15) Calahorro AM (16) Louhamane A (17) Fernandez J (18) Sanz-Pamplona R (19) Watkins TBK (20) Galvao V (21) Munoz-Couselo E (22) Ros J (23) ƒlez E (24) Oliveira M (25) Saura Manich C (26) Brana I (27) Oaknin A (28) Alemany R (29) Tabernero J (30) Perez-Lopez R (31) Turcotte S (32) Frankell AM (33) Garralda E (34) Toledo RA (35) Gros A

Cancer discovery

To expand the accessibility of neoantigen-based immunotherapy, Garcia-Garijo et al. integrated circulating tumor DNA (ctDNA) whole-exome sequencing (WES) to identify non-synonymous mutations (NSMs) with the isolation of neoantigen-specific T cells from circulating CD8+PD1hiCD38+ and CD4+PD1hi populations. In 8 patients with metastatic solid cancers, this strategy identified most lesion-derived NSMs (and additional neoantigens) enriched for clonal variants. In a cohort of 69 patients with metastatic solid cancers, neoantigen discovery based only on ctDNA seemed feasible in ~50% of patients (~85% of patients with colorectal cancer).

Contributed by Ute Burkhardt

(1) Garcia-Garijo A (2) Creus-Gonz‡lez I (3) Levy PL (4) Moreno-C‡rdenas AB (5) Prieto-Fern‡ndez E (6) Lozano-Rabella M (7) Fajardo CA (8) Pujol-Borrell R (9) Mar’n-Bayo A (10) Kusnick J (11) Gonzalez J (12) Brujas C (13) Gartner JJ (14) Yuste-Estevanez A (15) Calahorro AM (16) Louhamane A (17) Fernandez J (18) Sanz-Pamplona R (19) Watkins TBK (20) Galvao V (21) Munoz-Couselo E (22) Ros J (23) ƒlez E (24) Oliveira M (25) Saura Manich C (26) Brana I (27) Oaknin A (28) Alemany R (29) Tabernero J (30) Perez-Lopez R (31) Turcotte S (32) Frankell AM (33) Garralda E (34) Toledo RA (35) Gros A

Cancer discovery

To expand the accessibility of neoantigen-based immunotherapy, Garcia-Garijo et al. integrated circulating tumor DNA (ctDNA) whole-exome sequencing (WES) to identify non-synonymous mutations (NSMs) with the isolation of neoantigen-specific T cells from circulating CD8+PD1hiCD38+ and CD4+PD1hi populations. In 8 patients with metastatic solid cancers, this strategy identified most lesion-derived NSMs (and additional neoantigens) enriched for clonal variants. In a cohort of 69 patients with metastatic solid cancers, neoantigen discovery based only on ctDNA seemed feasible in ~50% of patients (~85% of patients with colorectal cancer).

Contributed by Ute Burkhardt

ABSTRACT: Neoantigen-targeted T-cell therapies require invasive tumor biopsies to identify neoantigens and reactive T cells, limiting their applicability and potentially underestimating tumor heterogeneity. We propose a novel strategy relying solely on peripheral blood to identify non-synonymous mutations via cell-free DNA whole-exome sequencing and isolate neoantigen-specific CD4+ and CD8+ T cells based on PD-1 and CD39 co-expression. Our method identified most neoantigens and increased the number of T-cell reactivities detected by standard biopsy-based techniques in an initial cohort of eight metastatic cancer patients. Critically, our approach uncovered additional neoantigens missed by tumor biopsy analysis, highlighting the potential for broader neoantigen targeting using liquid biopsies. Analysis of a cohort of 69 metastatic cancer patients revealed that approximately half could be eligible for our blood-only approach. This proof-of-concept study demonstrates the potential of using blood as a surrogate or complement for tumor biopsies to develop neoantigen-reactive T-cell therapies against a broader spectrum of neoantigens.

Author Info: (1) Vall d'Hebron Institute of Oncology Barcelona, Barcelona Spain. ROR: https://ror.org/054xx3904 (2) Vall d'Hebron Institute of Oncology Barcelona, Barcelona Spain. ROR: https://

Author Info: (1) Vall d'Hebron Institute of Oncology Barcelona, Barcelona Spain. ROR: https://ror.org/054xx3904 (2) Vall d'Hebron Institute of Oncology Barcelona, Barcelona Spain. ROR: https://ror.org/054xx3904 (3) Vall d'Hebron Institute of Oncology Barcelona, Barcelona Spain. ROR: https://ror.org/054xx3904 (4) Vall d'Hebron Institute of Oncology Spain. ROR: https://ror.org/054xx3904 (5) Vall d'Hebron Institute of Oncology Barcelona, Barcelona Spain. ROR: https://ror.org/054xx3904 (6) Vall d'Hebron Institute of Oncology Barcelona, Barcelona Spain. ROR: https://ror.org/054xx3904 (7) Vall d'Hebron Institute of Oncology Barcelona, Barcelona Spain. ROR: https://ror.org/054xx3904 (8) Universitat Aut˜noma de Barcelona Barcelona, Barcelona Spain. ROR: https://ror.org/052g8jq94 (9) Vall d'Hebron Institute of Oncology Barcelona, Barcelona Spain. ROR: https://ror.org/054xx3904 (10) Vall d'Hebron Institute of Oncology Barcelona, Barcelona Spain. ROR: https://ror.org/054xx3904 (11) Vall d'Hebron Institute of Oncology Barcelona, Barcelona Spain. ROR: https://ror.org/054xx3904 (12) Vall d'Hebron Institute of Oncology Barcelona, Barcelona Spain. ROR: https://ror.org/054xx3904 (13) National Institutes of Health United States. ROR: https://ror.org/01cwqze88 (14) Vall d'Hebron Institute of Oncology Barcelona, Barcelona Spain. ROR: https://ror.org/054xx3904 (15) Vall d'Hebron Institute of Oncology Barcelona, Barcelona Spain. ROR: https://ror.org/054xx3904 (16) Vall d'Hebron Institute of Oncology Barcelona, Barcelona Spain. ROR: https://ror.org/054xx3904 (17) Vall d'Hebron Institute of Oncology Barcelona, Barcelona Spain. ROR: https://ror.org/054xx3904 (18) Instituto de Investigaci—n Sanitaria Arag—n Zaragoza Spain. ROR: https://ror.org/03njn4610 (19) Stanford University Stanford, CA United States. ROR: https://ror.org/00f54p054 (20) Vall d'Hebron Institute of Oncology Barcelona Spain. ROR: https://ror.org/054xx3904 (21) Vall d'Hebron Institute of Oncology barcelona, barcelona, spain Spain. ROR: https://ror.org/054xx3904 (22) Vall d'Hebron Institute of Oncology (VHIO) Barcelona Spain. (23) Vall d'Hebron Institute of Oncology Barcelona, Barcelona Spain. ROR: https://ror.org/054xx3904 (24) Vall d'Hebron Institute of Oncology Barcelona Spain. ROR: https://ror.org/054xx3904 (25) Vall d'Hebron Institute of Oncology Barcelona, Barcelona Spain. ROR: https://ror.org/054xx3904 (26) Vall d'Hebron Institute of Oncology Barcelona, Barcelona Spain. ROR: https://ror.org/054xx3904 (27) Vall d'Hebron Institute of Oncology Barcelona Spain. ROR: https://ror.org/054xx3904 (28) Institut d'Investigaci— BiomŽdica de Bellvitge L'Hospitalet de Llobregat Spain. ROR: https://ror.org/0008xqs48 (29) Vall d'Hebron Institute of Oncology Barcelona Spain. ROR: https://ror.org/054xx3904 (30) Vall d'Hebron Institute of Oncology Barcelona, Barcelona Spain. ROR: https://ror.org/054xx3904 (31) Centre Hospitalier de l'UniversitŽ de MontrŽal Montreal Canada. ROR: https://ror.org/0410a8y51 (32) The Francis Crick Institute London United Kingdom. ROR: https://ror.org/04tnbqb63 (33) Vall d'Hebron Institute of Oncology Barcelona Spain. ROR: https://ror.org/054xx3904 (34) Vall d'Hebron Institute of Oncology Barcelona, Barcelona Spain. ROR: https://ror.org/054xx3904 (35) Vall d'Hebron Institute of Oncology Barcelona, Barcelona Spain. ROR: https://ror.org/054xx3904

Citation: Cancer Discov 2026 Sep 29 Epub09/29/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42806482

Tags:

Spatially confined IL-12 programs CAR-NK through mTORC1 to coordinate antitumor immune networks Spotlight 

(1) Tarannum M (2) Dinh K (3) Stanojevic M (4) Nguyen M (5) Campisi M (6) Maia A (7) Liu F (8) Yang S (9) Birch GC (10) Bobilev E (11) Gillanders I (12) Sheffer M (13) Gupta S (14) Wang J (15) Ganapathy S (16) Michaud DE (17) Dalton GN (18) Chugh S (19) Nguyen QD (20) Paweletz CP (21) Gokhale PC (22) Gao Y (23) Cancelas J (24) Guerriero JL (25) Choueiri TK (26) Barbie DA (27) Aguirre AJ (28) Porter RL (29) Matulonis UA (30) Koreth J (31) Wu CJ (32) Soiffer RJ (33) Ritz J (34) Chen J (35) Romee R

Cancer discovery

Tarannum et al. engineered mesothelin-targeted CAR-NK cells secreting IL-12 tethered to a collagen-binding A3 domain to spatially restrict IL-12 activity within the collagen I/III-rich TIME. IL-12 and CAR signaling converged through Ras-ERK and PI3K pathways to sustain mTORC1 activity, enhancing CAR-NK cell activation, proliferation, and metabolic fitness. Matrix-anchored IL-12 CAR-NK cells also activated bystander NK cells, T cells, and macrophages, without expanding Tregs. In ovarian and pancreatic cancer models, IL-12 CAR-NK cells achieved potent and durable antitumor responses, with limited systemic IL-12 toxicity.

Contributed by Shishir Pant

(1) Tarannum M (2) Dinh K (3) Stanojevic M (4) Nguyen M (5) Campisi M (6) Maia A (7) Liu F (8) Yang S (9) Birch GC (10) Bobilev E (11) Gillanders I (12) Sheffer M (13) Gupta S (14) Wang J (15) Ganapathy S (16) Michaud DE (17) Dalton GN (18) Chugh S (19) Nguyen QD (20) Paweletz CP (21) Gokhale PC (22) Gao Y (23) Cancelas J (24) Guerriero JL (25) Choueiri TK (26) Barbie DA (27) Aguirre AJ (28) Porter RL (29) Matulonis UA (30) Koreth J (31) Wu CJ (32) Soiffer RJ (33) Ritz J (34) Chen J (35) Romee R

Cancer discovery

Tarannum et al. engineered mesothelin-targeted CAR-NK cells secreting IL-12 tethered to a collagen-binding A3 domain to spatially restrict IL-12 activity within the collagen I/III-rich TIME. IL-12 and CAR signaling converged through Ras-ERK and PI3K pathways to sustain mTORC1 activity, enhancing CAR-NK cell activation, proliferation, and metabolic fitness. Matrix-anchored IL-12 CAR-NK cells also activated bystander NK cells, T cells, and macrophages, without expanding Tregs. In ovarian and pancreatic cancer models, IL-12 CAR-NK cells achieved potent and durable antitumor responses, with limited systemic IL-12 toxicity.

Contributed by Shishir Pant

ABSTRACT: Solid tumors evade immunotherapy because of immunosuppressive microenvironments that limit immune cell persistence and function. Although interleukin-12 (IL-12) potently activates antitumor immunity, its clinical use has been constrained by systemic toxicity. Here we engineered a CAR natural killer (NK) cell platform that integrated IL-12 signaling to enhance antitumor immunity. IL-12 signaling synergized with CAR activation to sustain mTORC1 activity through convergent Ras-ERK and PI3K pathways, promoting metabolic fitness, autonomous expansion, and sustained effector function. IL-12 also activated bystander NK cells, T cells, and macrophages to remodel the tumor microenvironment. To improve safety, IL-12 was tethered to a collagen-binding A3-domain, restricting its activity to the extracellular matrix and limiting systemic exposure. In ovarian and pancreatic cancer models, matrix-anchored IL-12 CAR NK cells expanded without exogenous cytokines and achieved durable tumor control. These findings suggest that mTORC1-mediated integration of CAR and cytokine signaling can enhance immune fitness and overcome immunosuppressive tumor microenvironments.

Author Info: (1) Dana-Farber Cancer Institute Boston, MA United States. ROR: https://ror.org/02jzgtq86 (2) Dana-Farber Cancer Institute Boston, MA United States. ROR: https://ror.org/02jzgtq86

Author Info: (1) Dana-Farber Cancer Institute Boston, MA United States. ROR: https://ror.org/02jzgtq86 (2) Dana-Farber Cancer Institute Boston, MA United States. ROR: https://ror.org/02jzgtq86 (3) University of Pittsburgh Pittsburgh, PA United States. ROR: https://ror.org/01an3r305 (4) Dana-Farber Cancer Institute United States. ROR: https://ror.org/02jzgtq86 (5) Dana-Farber Cancer Institute Boston, MA United States. ROR: https://ror.org/02jzgtq86 (6) Dana-Farber Cancer Institute Boston, MA United States. ROR: https://ror.org/02jzgtq86 (7) Dana Farber Cancer Institute Boston United States. (8) Dana-Farber Cancer Institute United States. ROR: https://ror.org/02jzgtq86 (9) Dana-Farber Cancer Institute Boston, MA United States. ROR: https://ror.org/02jzgtq86 (10) Dana-Farber Cancer Institute Boston, MA United States. ROR: https://ror.org/02jzgtq86 (11) Dana-Farber Cancer Institute Boston, MA United States. ROR: https://ror.org/02jzgtq86 (12) Dana-Farber Cancer Institute Boston, MA United States. ROR: https://ror.org/02jzgtq86 (13) Dana-Farber Cancer Institute Boston, MA United States. ROR: https://ror.org/02jzgtq86 (14) Dana-Farber Brigham Cancer Center Boston, MA United States. ROR: https://ror.org/05rgrbr06 (15) Dana-Farber Cancer Institute Boston United States. ROR: https://ror.org/02jzgtq86 (16) Dana-Farber Cancer Institute Boston, MA United States. ROR: https://ror.org/02jzgtq86 (17) Dana-Farber Cancer Institute United States. (18) Dana-Farber Cancer Institute Boston, MA United States. ROR: https://ror.org/02jzgtq86 (19) Dana-Farber Cancer Institute Boston, MA United States. ROR: https://ror.org/02jzgtq86 (20) Dana-Farber Cancer Institute Boston, Massachusetts United States. ROR: https://ror.org/02jzgtq86 (21) Dana-Farber Cancer Institute Boston United States. ROR: https://ror.org/02jzgtq86 (22) Skyline Therapeutics Cambridge, MA United States. (23) University of Cincinnati Medical Center Cincinnati United States. ROR: https://ror.org/02p72h367 (24) Dana-Farber Cancer Institute Boston, MA United States. ROR: https://ror.org/02jzgtq86 (25) Dana-Farber Cancer Institute Boston, MA United States. ROR: https://ror.org/02jzgtq86 (26) Dana-Farber Cancer Institute Boston, MA United States. ROR: https://ror.org/02jzgtq86 (27) Dana-Farber Cancer Institute Boston, MA United States. ROR: https://ror.org/02jzgtq86 (28) Dana-Farber Cancer Institute Boston, MA United States. ROR: https://ror.org/02jzgtq86 (29) Dana-Farber Cancer Institute Boston, Massachusetts United States. ROR: https://ror.org/02jzgtq86 (30) Dana-Farber Cancer Institute Boston United States. ROR: https://ror.org/02jzgtq86 (31) Dana-Farber Cancer Institute Boston, MA United States. ROR: https://ror.org/02jzgtq86 (32) Dana-Farber Cancer Institute Boston, MA United States. ROR: https://ror.org/02jzgtq86 (33) Dana-Farber Cancer Institute Boston, MA United States. ROR: https://ror.org/02jzgtq86 (34) Massachusetts Institute of Technology Cambridge, MA United States. ROR: https://ror.org/042nb2s44 (35) Dana-Farber Cancer Institute, Harvard University Boston, MA United States.

Citation: Cancer Discov 2026 Sep 29 Epub09/29/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42810409

Tags:

Computational design of optimized and preferentially paired human TCR constant regions for improved T cell function Spotlight 

(1) Radman M (2) Shamul-Raybi A (3) Parker J (4) Fleishman SJ (5) Cohen CJ

Science advances | Free PMC Article

Using a computational strategy, Radman et al. mutated the constant and transmembrane regions of the MART-1 DMF4 TCR α/β chains to reduce mispairing and improve expression. TCR variants were found that increased expression and TNFα production against MART-1+ cells compared to the WT TCR, and the modified α/β chains expressed better together than with their WT counterparts. Modified TCR-T cells generated by retroviral vector had superior cytokine production to WT TCR-T (in bulk T cells and CD4+ or CD8+ T cells), as well as cytotoxicity and in vivo efficacy. This same strategy was successfully applied to other antitumor and antiviral TCRs.

Contributed by Alex Najibi

(1) Radman M (2) Shamul-Raybi A (3) Parker J (4) Fleishman SJ (5) Cohen CJ

Science advances | Free PMC Article

Using a computational strategy, Radman et al. mutated the constant and transmembrane regions of the MART-1 DMF4 TCR α/β chains to reduce mispairing and improve expression. TCR variants were found that increased expression and TNFα production against MART-1+ cells compared to the WT TCR, and the modified α/β chains expressed better together than with their WT counterparts. Modified TCR-T cells generated by retroviral vector had superior cytokine production to WT TCR-T (in bulk T cells and CD4+ or CD8+ T cells), as well as cytotoxicity and in vivo efficacy. This same strategy was successfully applied to other antitumor and antiviral TCRs.

Contributed by Alex Najibi

ABSTRACT: T cell receptor (TCR) gene transfer is a promising approach for cancer immunotherapy, but its efficacy is limited by mispairing of TCR chains, which reduces surface expression and may generate off-target specificities. We applied the PROSS and FuncLib algorithms to engineer human TCR constant regions for improved stability and preferential pairing. After several screening rounds, we identified a variant, termed structurally enhanced TCR (SET), that exhibited markedly enhanced surface expression, functional avidity, and reduced mispairing. SET-expressing T cells secreted higher cytokine levels, displayed increased activation, and mediated superior cytotoxicity. Notably, SET demonstrated function in CD4(+) T cells and mediated potent tumor control in xenograft models, significantly delaying tumor growth and improving survival. SET's benefits were reproducible across six different TCRs, supporting its broad applicability. These findings highlight the potential of rational design to improve the potency of TCR-based therapies.

Author Info: (1) The Laboratory of Tumor Immunology and Immunotherapy, The Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat Gan, Israel. (2) The Laboratory of Tumor

Author Info: (1) The Laboratory of Tumor Immunology and Immunotherapy, The Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat Gan, Israel. (2) The Laboratory of Tumor Immunology and Immunotherapy, The Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat Gan, Israel. (3) Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot, Israel. (4) Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot, Israel. (5) The Laboratory of Tumor Immunology and Immunotherapy, The Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat Gan, Israel.

Citation: Sci Adv 2026 Sep 25 12:eaeb9189 Epub09/23/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42777048

Tags:

Functional evaluation of TCR-pMHC pairs at scale allows in silico TCR reactivity prediction Featured  

(1) Messemaker M (2) Kwee BPY (3) Moravec _ (4) de Paauw S (5) Urbanus J (6) çlvarez-Salmoral D (7) Geerligs J (8) Xie R (9) Voogd R (10) Morris B (11) Guislain A (12) Winkler Y (13) Richterich CA (14) Mussmann M (15) Bakker M (16) Steinmetz M (17) Iras M (18) Marcus E (19) Teuwen J (20) Perrakis A (21) Beijersbergen RL (22) Scheper W (23) Schumacher TN

Immunity

Messemaker and Kwee et al. developed a TCR rapid assembly platform (T-RAP) and used it to generate a dataset of functionally validated TCR-pMHC pairs, which enabled the assembly of diverse and standardized TCR libraries and allowed for structure-based prediction of TCR-pMHC reactivity. Pooled screening of these TCR libraries could then be used to evaluate the quality of existing reactivity prediction models, including tcrdist3 and AlphaFold3, showed strong capacities for distinguishing reactivity and could be used both to pair TCRs with cognate pMHC epitopes and to shortlist TCRs with reactivity to patient-specific neoantigens, without any task-specific training.

(1) Messemaker M (2) Kwee BPY (3) Moravec _ (4) de Paauw S (5) Urbanus J (6) çlvarez-Salmoral D (7) Geerligs J (8) Xie R (9) Voogd R (10) Morris B (11) Guislain A (12) Winkler Y (13) Richterich CA (14) Mussmann M (15) Bakker M (16) Steinmetz M (17) Iras M (18) Marcus E (19) Teuwen J (20) Perrakis A (21) Beijersbergen RL (22) Scheper W (23) Schumacher TN

Immunity

Messemaker and Kwee et al. developed a TCR rapid assembly platform (T-RAP) and used it to generate a dataset of functionally validated TCR-pMHC pairs, which enabled the assembly of diverse and standardized TCR libraries and allowed for structure-based prediction of TCR-pMHC reactivity. Pooled screening of these TCR libraries could then be used to evaluate the quality of existing reactivity prediction models, including tcrdist3 and AlphaFold3, showed strong capacities for distinguishing reactivity and could be used both to pair TCRs with cognate pMHC epitopes and to shortlist TCRs with reactivity to patient-specific neoantigens, without any task-specific training.

ABSTRACT: Accurate prediction of T cell receptor (TCR) reactivity is a long-standing goal in immunology. Here, we asked whether functional validation of TCR-peptide-major histocompatibility complex (MHC) (TCR-pMHC) pairs at scale alters performance estimates of TCR-pMHC reactivity prediction models. We developed a TCR rapid assembly platform (T-RAP) that allowed the generation of large and uniform TCR libraries. T-RAP enabled evaluation of TCR signaling or MHC multimer binding of thousands of previously reported TCR-pMHC pairs under standardized conditions. In this setting of systematic standardized evaluation, only _50% of these TCRs showed the previously reported TCR reactivity. Notably, AlphaFold3 structural predictions showed good performance in identifying reactive TCR-pMHC pairs within the set of TCRs that experimentally validated without any task-specific training. AlphaFold3 structural predictions could likewise be used to shortlist TCRs reactive to patient-specific cancer neoantigens. In silico prediction of TCR-pMHC reactivity thus has greater feasibility than previously assumed, with implications for basic research and clinical application.

Author Info: (1) Division of Molecular Oncology & Immunology, The Netherlands Cancer Institute, Amsterdam, the Netherlands; Oncode Institute, Utrecht, the Netherlands. (2) Division of Molecular

Author Info: (1) Division of Molecular Oncology & Immunology, The Netherlands Cancer Institute, Amsterdam, the Netherlands; Oncode Institute, Utrecht, the Netherlands. (2) Division of Molecular Oncology & Immunology, The Netherlands Cancer Institute, Amsterdam, the Netherlands; Oncode Institute, Utrecht, the Netherlands. (3) Division of Molecular Oncology & Immunology, The Netherlands Cancer Institute, Amsterdam, the Netherlands. (4) Division of Molecular Oncology & Immunology, The Netherlands Cancer Institute, Amsterdam, the Netherlands; Oncode Institute, Utrecht, the Netherlands. (5) Division of Molecular Oncology & Immunology, The Netherlands Cancer Institute, Amsterdam, the Netherlands; Oncode Institute, Utrecht, the Netherlands. (6) Oncode Institute, Utrecht, the Netherlands; Division of Biochemistry, The Netherlands Cancer Institute, Amsterdam, the Netherlands. (7) Division of Molecular Oncology & Immunology, The Netherlands Cancer Institute, Amsterdam, the Netherlands; Oncode Institute, Utrecht, the Netherlands; The NKI Robotics and Screening Center, The Netherlands Cancer Institute, Amsterdam, the Netherlands. (8) Oncode Institute, Utrecht, the Netherlands; Division of Biochemistry, The Netherlands Cancer Institute, Amsterdam, the Netherlands. (9) Division of Molecular Oncology & Immunology, The Netherlands Cancer Institute, Amsterdam, the Netherlands; Oncode Institute, Utrecht, the Netherlands. (10) The NKI Robotics and Screening Center, The Netherlands Cancer Institute, Amsterdam, the Netherlands. (11) Division of Molecular Oncology & Immunology, The Netherlands Cancer Institute, Amsterdam, the Netherlands; Oncode Institute, Utrecht, the Netherlands. (12) Division of Molecular Oncology & Immunology, The Netherlands Cancer Institute, Amsterdam, the Netherlands; Oncode Institute, Utrecht, the Netherlands. (13) Division of Molecular Oncology & Immunology, The Netherlands Cancer Institute, Amsterdam, the Netherlands; Oncode Institute, Utrecht, the Netherlands. (14) Division of Molecular Oncology & Immunology, The Netherlands Cancer Institute, Amsterdam, the Netherlands; Oncode Institute, Utrecht, the Netherlands. (15) Division of Molecular Oncology & Immunology, The Netherlands Cancer Institute, Amsterdam, the Netherlands; Oncode Institute, Utrecht, the Netherlands. (16) Division of Molecular Oncology & Immunology, The Netherlands Cancer Institute, Amsterdam, the Netherlands; Oncode Institute, Utrecht, the Netherlands. (17) Division of Molecular Oncology & Immunology, The Netherlands Cancer Institute, Amsterdam, the Netherlands; Oncode Institute, Utrecht, the Netherlands. (18) AI for Oncology, The Netherlands Cancer Institute, Amsterdam, the Netherlands. (19) AI for Oncology, The Netherlands Cancer Institute, Amsterdam, the Netherlands. (20) Oncode Institute, Utrecht, the Netherlands; Division of Biochemistry, The Netherlands Cancer Institute, Amsterdam, the Netherlands. (21) The NKI Robotics and Screening Center, The Netherlands Cancer Institute, Amsterdam, the Netherlands. (22) Division of Molecular Oncology & Immunology, The Netherlands Cancer Institute, Amsterdam, the Netherlands. (23) Division of Molecular Oncology & Immunology, The Netherlands Cancer Institute, Amsterdam, the Netherlands; Oncode Institute, Utrecht, the Netherlands; Department of Hematology, Leiden University Medical Center, Leiden, the Netherlands. Electronic address: t.schumacher@nki.nl.

Citation: Immunity 2026 Oct 1 Epub10/01/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42822443

Tags:

Rejuvenating endogenous antitumor immunity via a chimeric receptor-engineered oncolytic virus targeting tumor-associated macrophages Spotlight 

(1) Lin C (2) Li S (3) Lou R (4) Teng W (5) Tian Y (6) Feng C (7) Wang N (8) Rao Y (9) Qin Y (10) Li L (11) Huang X (12) Lin Y (13) Zhang J (14) Xia N (15) Huang C

Science advances | Free PMC Article

Lin et al. engineered an oncolytic herpesvirus (oHSV) with a PD-L1 nanobody attached to gD on the viral envelope surface (gDαPD- L1), targeting the virus to both tumors and TAMs expressing PD-L1. In addition to its oncolytic activity, this CAR-oHSV also resulted in the presentation of anti-PD-L1 CARs on infected cells, blocking PD-L1 in cis. In TAMs, CAR-oHSV killed a subset of TAMs, while remaining TAMs were reprogrammed via STING activation towards a CXCL9+ antigen-presenting phenotype that supported CD8+ T cell-mediated antitumor immunity. CAR-oHSV was well tolerated and showed synergy with checkpoint blockade and adoptive cell therapy.

Contributed by Lauren Hitchings

(1) Lin C (2) Li S (3) Lou R (4) Teng W (5) Tian Y (6) Feng C (7) Wang N (8) Rao Y (9) Qin Y (10) Li L (11) Huang X (12) Lin Y (13) Zhang J (14) Xia N (15) Huang C

Science advances | Free PMC Article

Lin et al. engineered an oncolytic herpesvirus (oHSV) with a PD-L1 nanobody attached to gD on the viral envelope surface (gDαPD- L1), targeting the virus to both tumors and TAMs expressing PD-L1. In addition to its oncolytic activity, this CAR-oHSV also resulted in the presentation of anti-PD-L1 CARs on infected cells, blocking PD-L1 in cis. In TAMs, CAR-oHSV killed a subset of TAMs, while remaining TAMs were reprogrammed via STING activation towards a CXCL9+ antigen-presenting phenotype that supported CD8+ T cell-mediated antitumor immunity. CAR-oHSV was well tolerated and showed synergy with checkpoint blockade and adoptive cell therapy.

Contributed by Lauren Hitchings

ABSTRACT: Immunosuppressive tumor-associated macrophages (TAMs) create a barrier to effective antitumor immunity and promote therapeutic resistance. Reeducating TAMs to enhance their antitumor capabilities through phenotypic remodeling remains challenging. Here, we report a modular oncolytic herpesvirus platform, engineered with a PD-L1-specific chimeric receptor integrated into the viral envelope protein (CAR-oHSV). This design endows the virus with dual tropism, enabling it to target both tumor cells and TAMs within the tumor microenvironment. In virus-resistant tumor models, CAR-oHSV preferentially targets PD-L1(+) TAMs and triggers a STING-dependent reprogramming into a CXCL9(+) phenotype, enhancing their tumor antigen cross-presentation capability and inducing an endogenous antitumor T cell response. Furthermore, this platform can synergize with adoptive T cell therapy and immune checkpoint blockade therapy to overcome immunotherapy resistance. Collectively, our findings define a precision-oncolytic platform that dismantles TAM-mediated immunosuppression while amplifying adaptive immunity, offering a promising translational avenue for cancer immunotherapy.

Author Info: (1) State Key Laboratory of Vaccines for Infectious Diseases, Department of Laboratory Medicine, School of Public Health, Xiamen University, Xiamen, 361102, China. National Institu

Author Info: (1) State Key Laboratory of Vaccines for Infectious Diseases, Department of Laboratory Medicine, School of Public Health, Xiamen University, Xiamen, 361102, China. National Institute of Diagnostics and Vaccine Development in Infectious Diseases, Xiang An Biomedicine Laboratory, Xiamen University, Xiamen, 361102, China. (2) State Key Laboratory of Vaccines for Infectious Diseases, Department of Laboratory Medicine, School of Public Health, Xiamen University, Xiamen, 361102, China. National Institute of Diagnostics and Vaccine Development in Infectious Diseases, Xiang An Biomedicine Laboratory, Xiamen University, Xiamen, 361102, China. (3) State Key Laboratory of Vaccines for Infectious Diseases, Department of Laboratory Medicine, School of Public Health, Xiamen University, Xiamen, 361102, China. National Institute of Diagnostics and Vaccine Development in Infectious Diseases, Xiang An Biomedicine Laboratory, Xiamen University, Xiamen, 361102, China. (4) State Key Laboratory of Vaccines for Infectious Diseases, Department of Laboratory Medicine, School of Public Health, Xiamen University, Xiamen, 361102, China. National Institute of Diagnostics and Vaccine Development in Infectious Diseases, Xiang An Biomedicine Laboratory, Xiamen University, Xiamen, 361102, China. (5) State Key Laboratory of Vaccines for Infectious Diseases, Department of Laboratory Medicine, School of Public Health, Xiamen University, Xiamen, 361102, China. National Institute of Diagnostics and Vaccine Development in Infectious Diseases, Xiang An Biomedicine Laboratory, Xiamen University, Xiamen, 361102, China. (6) State Key Laboratory of Vaccines for Infectious Diseases, Department of Laboratory Medicine, School of Public Health, Xiamen University, Xiamen, 361102, China. National Institute of Diagnostics and Vaccine Development in Infectious Diseases, Xiang An Biomedicine Laboratory, Xiamen University, Xiamen, 361102, China. (7) State Key Laboratory of Vaccines for Infectious Diseases, Department of Laboratory Medicine, School of Public Health, Xiamen University, Xiamen, 361102, China. National Institute of Diagnostics and Vaccine Development in Infectious Diseases, Xiang An Biomedicine Laboratory, Xiamen University, Xiamen, 361102, China. (8) State Key Laboratory of Vaccines for Infectious Diseases, Department of Laboratory Medicine, School of Public Health, Xiamen University, Xiamen, 361102, China. National Institute of Diagnostics and Vaccine Development in Infectious Diseases, Xiang An Biomedicine Laboratory, Xiamen University, Xiamen, 361102, China. (9) State Key Laboratory of Vaccines for Infectious Diseases, Department of Laboratory Medicine, School of Public Health, Xiamen University, Xiamen, 361102, China. National Institute of Diagnostics and Vaccine Development in Infectious Diseases, Xiang An Biomedicine Laboratory, Xiamen University, Xiamen, 361102, China. (10) State Key Laboratory of Vaccines for Infectious Diseases, Department of Laboratory Medicine, School of Public Health, Xiamen University, Xiamen, 361102, China. National Institute of Diagnostics and Vaccine Development in Infectious Diseases, Xiang An Biomedicine Laboratory, Xiamen University, Xiamen, 361102, China. (11) State Key Laboratory of Vaccines for Infectious Diseases, Department of Laboratory Medicine, School of Public Health, Xiamen University, Xiamen, 361102, China. National Institute of Diagnostics and Vaccine Development in Infectious Diseases, Xiang An Biomedicine Laboratory, Xiamen University, Xiamen, 361102, China. (12) State Key Laboratory of Vaccines for Infectious Diseases, Department of Laboratory Medicine, School of Public Health, Xiamen University, Xiamen, 361102, China. National Institute of Diagnostics and Vaccine Development in Infectious Diseases, Xiang An Biomedicine Laboratory, Xiamen University, Xiamen, 361102, China. (13) State Key Laboratory of Vaccines for Infectious Diseases, Department of Laboratory Medicine, School of Public Health, Xiamen University, Xiamen, 361102, China. National Institute of Diagnostics and Vaccine Development in Infectious Diseases, Xiang An Biomedicine Laboratory, Xiamen University, Xiamen, 361102, China. (14) State Key Laboratory of Vaccines for Infectious Diseases, Department of Laboratory Medicine, School of Public Health, Xiamen University, Xiamen, 361102, China. National Institute of Diagnostics and Vaccine Development in Infectious Diseases, Xiang An Biomedicine Laboratory, Xiamen University, Xiamen, 361102, China. School of Life Sciences, Xiamen University, Xiamen, 361102, China. (15) State Key Laboratory of Vaccines for Infectious Diseases, Department of Laboratory Medicine, School of Public Health, Xiamen University, Xiamen, 361102, China. National Institute of Diagnostics and Vaccine Development in Infectious Diseases, Xiang An Biomedicine Laboratory, Xiamen University, Xiamen, 361102, China.

Citation: Sci Adv 2026 Sep 18 12:eaef6767 Epub09/18/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42758830

Tags:

Inducible IL-12 or IL-18 secreting CAR T cells targeting the glyco-antigen CD176 exhibit potent activity against non-small cell lung cancer in preclinical models Spotlight 

(1) Malinconico C (2) Weber J (3) Polzien AJ (4) Bonifacius A (5) Umland M (6) Deveuve Q (7) Bargmann T (8) Zimmermann K (9) Gellert J (10) Neubert L (11) DŸbel S (12) Schambach A (13) Braun A (14) Blasczyk R (15) Abken H (16) Hudecek M (17) Dragon AC (18) Eiz-Vesper B

Cancer immunology research

Malinconico et al. engineered T cells with both a CAR targeting CD176 (expressed in NSCLC and other tumors), and an inducible cassette encoding either IL-18 or IL-12 that would be expressed following CAR activation of NF-κB. The resulting CD176-iIL18 or CD176-iIL12 TRUCKs showed antigen-dependent secretion of IL-18/IL-12, increased effector molecules, and heightened THP-1 monocyte chemoattraction. They also showed increased cytotoxicity and antitumor activity in vitro, against patient explants, and in vivo, and performed best when both CD4+ and CD8+ T cells were included. TRUCKs producing IL-12 outperformed those producing IL-18, but with more toxicity.

Contributed by Lauren Hitchings

(1) Malinconico C (2) Weber J (3) Polzien AJ (4) Bonifacius A (5) Umland M (6) Deveuve Q (7) Bargmann T (8) Zimmermann K (9) Gellert J (10) Neubert L (11) DŸbel S (12) Schambach A (13) Braun A (14) Blasczyk R (15) Abken H (16) Hudecek M (17) Dragon AC (18) Eiz-Vesper B

Cancer immunology research

Malinconico et al. engineered T cells with both a CAR targeting CD176 (expressed in NSCLC and other tumors), and an inducible cassette encoding either IL-18 or IL-12 that would be expressed following CAR activation of NF-κB. The resulting CD176-iIL18 or CD176-iIL12 TRUCKs showed antigen-dependent secretion of IL-18/IL-12, increased effector molecules, and heightened THP-1 monocyte chemoattraction. They also showed increased cytotoxicity and antitumor activity in vitro, against patient explants, and in vivo, and performed best when both CD4+ and CD8+ T cells were included. TRUCKs producing IL-12 outperformed those producing IL-18, but with more toxicity.

Contributed by Lauren Hitchings

ABSTRACT: To date, non-small cell lung cancer (NSCLC) remains the leading cause of cancer-related deaths worldwide, underscoring the urgent need for new treatment options. The oncofetal carbohydrate CD176 is masked on healthy tissues but is present on a variety of cancer entities and is associated with cancer invasiveness and metastasis. In this study, we employed chimeric antigen receptor T cells (CAR-Ts) directed against CD176 for treatment of NSCLC. CD176-CAR-Ts were optimized with an additional inducible cassette encoding IL-18 (CD176-iIL18-TRUCKs) or IL-12 (CD176-iIL12-TRUCKs) to augment antitumor reactivity through autocrine and paracrine signaling. CD176-iIL18- and CD176-iIL12-TRUCKs eradicate NSCLC cells in a 3D tumor spheroid model and tissue slices derived from lung adenocarcinoma patients more potently than CD176-CAR-Ts. Administration of TRUCKs in a lung carcinoma xenograft mouse model results in partial or complete tumor eradication in all mice treated with CD176-iIL12-TRUCKs and in 50% of mice treated with CD176-iIL18-TRUCKs. This study highlights the potential of CD176 as a CAR-T-cell target and suggest CD176-CAR-Ts armored with IL-18 or IL-12 as promising new therapeutic approach for the treatment of NSCLC and several other CD176-positive cancer entities.

Author Info: (1) Italian Institute of Technology Napoli Italy. ROR: https://ror.org/042t93s57 (2) University Hospital WŸrzburg WŸrzburg Germany. (3) Hannover Medical School Hannover Germany. (4

Author Info: (1) Italian Institute of Technology Napoli Italy. ROR: https://ror.org/042t93s57 (2) University Hospital WŸrzburg WŸrzburg Germany. (3) Hannover Medical School Hannover Germany. (4) Medizinische Hochschule Hannover Hannover Germany. ROR: https://ror.org/00f2yqf98 (5) Hannover Medical School Hannover Germany. (6) UniversitŠtsklinikum WŸrzburg WŸrzburg Germany. (7) Fraunhofer Institute for Toxicology and Experimental Medicine Hannover, Lower Saxony Germany. ROR: https://ror.org/02byjcr11 (8) Medizinische Hochschule Hannover Hannover Germany. ROR: https://ror.org/00f2yqf98 (9) Glycotope GmbH Berlin Germany. (10) Medizinische Hochschule Hannover Hannover, Low Saxony Germany. ROR: https://ror.org/00f2yqf98 (11) Technische UniversitŠt Braunschweig Braunschweig Germany. ROR: https://ror.org/010nsgg66 (12) Medizinische Hochschule Hannover Hannover Germany. ROR: https://ror.org/00f2yqf98 (13) Fraunhofer Institute for Toxicology and Experimental Medicine Hannover, Lower Saxony Germany. ROR: https://ror.org/02byjcr11 (14) Medizinische Hochschule Hannover Hannover Germany. ROR: https://ror.org/00f2yqf98 (15) Leibniz Institute for Immunotherapy and Univ Regensberg Regensburg Germany. (16) UniversitŠtsklinikum WŸrzburg WŸrzburg Germany. ROR: https://ror.org/03pvr2g57 (17) Medizinische Hochschule Hannover Hannover Germany. ROR: https://ror.org/00f2yqf98 (18) Medizinische Hochschule Hannover Hannover Germany. ROR: https://ror.org/00f2yqf98

Citation: Cancer Immunol Res 2026 Sep 22 Epub09/22/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42770707

Tags:

Reprogramming engineered autologous T cells to overcome resistance in patients with Merkel cell carcinoma Spotlight 

(1) Asano Y (2) Veatch JR (3) Sung CJ (4) Tang TH (5) Mazziotta F (6) Natsuki S (7) McAfee M (8) Bakhtiari J (9) Lee B (10) Martin L (11) Rizzi A (12) Zhang T (13) Smith CW (14) Paulson KG (15) Schmitt TM (16) Newell EW (17) Elz AE (18) Chen DG (19) Su Y (20) Gustafson HH (21) Yeung CCS (22) Seaton B (23) Hunter D (24) Koelle DM (25) Bhatia S (26) Hall ET (27) Voillet V (28) Cao J (29) Gooley T (30) Greenberg PD (31) Gottardo R (32) Oda SK (33) Nghiem P (34) Chapuis AG

Science translational medicine

Asano, Veatch, and Sung et al. identified TCRMCC1, a high-avidity HLA-A*02:01-restricted TCR targeting Merkel cell polyomavirus large-T antigen and treated seven patients who had ICI-refractory metastatic MCC using autologous TCRMCC1-transduced T cells plus ICB. TTCR-MCC1 cells trafficked to tumors and induced regression in two patients, but HLA class I silencing limited activity. In one patient, delayed regression coincided with endogenous effector T cell activation and restored tumor HLA expression. TTCR-MCC1 cells armored with CD8αβ and a CD200R-CD28 switch receptor showed enhanced tumor infiltration, HLA expression, and control of HLA-low MCC in vivo.

Contributed by Shishir Pant

(1) Asano Y (2) Veatch JR (3) Sung CJ (4) Tang TH (5) Mazziotta F (6) Natsuki S (7) McAfee M (8) Bakhtiari J (9) Lee B (10) Martin L (11) Rizzi A (12) Zhang T (13) Smith CW (14) Paulson KG (15) Schmitt TM (16) Newell EW (17) Elz AE (18) Chen DG (19) Su Y (20) Gustafson HH (21) Yeung CCS (22) Seaton B (23) Hunter D (24) Koelle DM (25) Bhatia S (26) Hall ET (27) Voillet V (28) Cao J (29) Gooley T (30) Greenberg PD (31) Gottardo R (32) Oda SK (33) Nghiem P (34) Chapuis AG

Science translational medicine

Asano, Veatch, and Sung et al. identified TCRMCC1, a high-avidity HLA-A*02:01-restricted TCR targeting Merkel cell polyomavirus large-T antigen and treated seven patients who had ICI-refractory metastatic MCC using autologous TCRMCC1-transduced T cells plus ICB. TTCR-MCC1 cells trafficked to tumors and induced regression in two patients, but HLA class I silencing limited activity. In one patient, delayed regression coincided with endogenous effector T cell activation and restored tumor HLA expression. TTCR-MCC1 cells armored with CD8αβ and a CD200R-CD28 switch receptor showed enhanced tumor infiltration, HLA expression, and control of HLA-low MCC in vivo.

Contributed by Shishir Pant

ABSTRACT: Immune checkpoint inhibitors (ICIs) have transformed Merkel cell carcinoma (MCC) outcomes, but most patients with MCC develop resistance. We identified T cell receptor (TCR)MCC1, a highly avid, HLA-A*02:01-restricted TCR targeting the Merkel cell polyomavirus (MCPyV) oncoprotein large-T antigen15-23. Seven patients with ICI-refractory metastatic MCPyV+ MCC received TCRMCC1-transduced cells (TTCR-MCC1 cells) after lymphodepleting chemotherapy or HLA-enhancing interventions [radiation or interferon gamma-1b (Actimmune)], with concurrent ICIs (NCT03747484). TTCR-MCC1 cells trafficked to tumor sites and expressed a gene expression profile compatible with T cell activation, with tumor regression observed in two patients. However, therapeutic activity was limited by HLA class I silencing, a common mechanism of immune escape in MCC. In one patient, delayed tumor regression coincided with endogenous effector immune activation and restoration of MCC HLA expression, implying that robust local responses could reverse HLA silencing. To overcome this barrier, we engineered CD4 and CD8 TTCR-MCC1 cells to coexpress CD8αβ and a CD200R-CD28 switch receptor, enabling CD4 T cell engagement and T cell costimulation. These modifications enhanced tumor infiltration, increased HLA expression, and improved control of HLAlow MCC in vivo in mice. These findings support the feasibility of TCR-engineered cell therapy for MCPyV+ MCC and provide a blueprint for overcoming immune evasion via targeted localized enhancement of antigen presentation.

Author Info: (1) Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA. (2) Translational Science and Therapeutics Division, Fred Hutchinson Can

Author Info: (1) Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA. (2) Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA. Department of Medicine, University of Washington School of Medicine, Seattle, WA 98195, USA. (3) Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA. (4) Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA. (5) Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA. Department of Medicine, University of Washington School of Medicine, Seattle, WA 98195, USA. (6) Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA. (7) Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA. (8) Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA. Department of Laboratory Medicine and Pathology, University of Washington School of Medicine, Seattle, WA 98195, USA. (9) Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA. (10) Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA. (11) Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA. (12) Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA. (13) Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA. (14) Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA. Department of Medicine, University of Washington School of Medicine, Seattle, WA 98195, USA. (15) Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA. (16) Department of Laboratory Medicine and Pathology, University of Washington School of Medicine, Seattle, WA 98195, USA. Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA. (17) Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA. (18) Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA. (19) Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA. Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA. (20) Department of Pediatrics, University of Washington School of Medicine, Seattle, WA 98195, USA. Ben Towne Center for Childhood Cancer and Blood Disorders Research, Seattle Children's Research Institute, Seattle, WA 98105, USA. (21) Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA. Department of Laboratory Medicine and Pathology, University of Washington School of Medicine, Seattle, WA 98195, USA. (22) Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA. (23) Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA. (24) Department of Medicine, University of Washington School of Medicine, Seattle, WA 98195, USA. Department of Laboratory Medicine and Pathology, University of Washington School of Medicine, Seattle, WA 98195, USA. Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA. Department of Global Health, University of Washington School of Medicine, Seattle, WA 98195, USA. Benaroya Research Institute, Seattle, WA 98101, USA. (25) Department of Medicine, University of Washington School of Medicine, Seattle, WA 98195, USA. Clinical Research Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA. (26) Department of Medicine, University of Washington School of Medicine, Seattle, WA 98195, USA. Clinical Research Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA. (27) Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA. (28) Shared Resources, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA. (29) Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA. (30) Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA. Department of Medicine, University of Washington School of Medicine, Seattle, WA 98195, USA. Department of Immunology, University of Washington School of Medicine, Seattle, WA 98195, USA. Parker Institute for Cancer Immunotherapy, San Francisco, CA 94129, USA. (31) Biomedical Data Science Center, Centre Hospitalier Universitaire Vaudois, 1010 Lausanne, Switzerland. University of Lausanne, 1015 Lausanne, Switzerland. School of Life Sciences, EPFL, 1015 Lausanne, Switzerland. (32) Department of Pediatrics, University of Washington School of Medicine, Seattle, WA 98195, USA. Ben Towne Center for Childhood Cancer and Blood Disorders Research, Seattle Children's Research Institute, Seattle, WA 98105, USA. (33) Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA. Department of Medicine, University of Washington School of Medicine, Seattle, WA 98195, USA. Department of Dermatology, University of Washington School of Medicine, Seattle, WA 98195, USA. (34) Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA. Department of Medicine, University of Washington School of Medicine, Seattle, WA 98195, USA.

Citation: Sci Transl Med 2026 Sep 9 18:eaea8773 Epub09/09/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42715345

Tags:

γδ T cells modulate anti-tumor immunity in small cell lung cancer

Spotlight 

(1) Ng J (2) You Y (3) Zhang TZ (4) Hess JB (5) Best SA (6) Caneborg A (7) Schmiel M (8) Diepstraten ST (9) Spelman T (10) Gray JI (11) Godfrey DI (12) Wu Y (13) Tothill RW (14) Anttila CJA (15) Baldwin TM (16) Naik SH (17) Amann-Zalcenstein D (18) Kersbergen AJ (19) Leong TL (20) George J (21) Ritchie ME (22) Gherardin NA (23) Koay HF (24) Hickey PF (25) Steinfort D (26) Sutherland KD

Cancer cell

Using scRNA sequencing, Ng et al. compared LN biopsy samples (non-affected vs. tumor-affected) from SCLC patients to study the antitumor role of MHC-I-independent pathways. Despite being PD-1+, γδ T cells were cytotoxic, infiltrated patient samples, and predicted better outcomes with anti-PD-L1 in patients with high levels of γδ T cells. In preclinical models, γδ T cells were as effective as CD8+ T cells in tarlatamab (DLL3–CD3 BiTE)-redirected SCLC killing, while zoledronate sensitized SCLC cells to Vδ2+ T cell-mediated killing and promoted spontaneous γδ T cell-mediated MHC-I-independent SCLC killing that required BTN2A1.

Contributed by Katherine Turner

(1) Ng J (2) You Y (3) Zhang TZ (4) Hess JB (5) Best SA (6) Caneborg A (7) Schmiel M (8) Diepstraten ST (9) Spelman T (10) Gray JI (11) Godfrey DI (12) Wu Y (13) Tothill RW (14) Anttila CJA (15) Baldwin TM (16) Naik SH (17) Amann-Zalcenstein D (18) Kersbergen AJ (19) Leong TL (20) George J (21) Ritchie ME (22) Gherardin NA (23) Koay HF (24) Hickey PF (25) Steinfort D (26) Sutherland KD

Cancer cell

Using scRNA sequencing, Ng et al. compared LN biopsy samples (non-affected vs. tumor-affected) from SCLC patients to study the antitumor role of MHC-I-independent pathways. Despite being PD-1+, γδ T cells were cytotoxic, infiltrated patient samples, and predicted better outcomes with anti-PD-L1 in patients with high levels of γδ T cells. In preclinical models, γδ T cells were as effective as CD8+ T cells in tarlatamab (DLL3–CD3 BiTE)-redirected SCLC killing, while zoledronate sensitized SCLC cells to Vδ2+ T cell-mediated killing and promoted spontaneous γδ T cell-mediated MHC-I-independent SCLC killing that required BTN2A1.

Contributed by Katherine Turner

ABSTRACT: Small cell lung cancer (SCLC) is a highly aggressive neoplasm with limited sensitivity to anti-PD-(L)1 blockade, which is likely caused by the epigenetic silencing of MHC-I. Elucidating MHC-I-independent immune recognition mechanisms is therefore crucial for enhancing treatment responses and improving clinical outcomes in a greater number of patients. Leveraging single-cell approaches, we discovered γδ T cell infiltration in biospecimens from patients with SCLC. Despite PD-1 expression, γδ T cells maintained a cytotoxic transcriptional profile, suggesting an anti-tumor role. Indeed, high γδ T cell infiltration in two practice-changing clinical trials predicted improved response to anti-PD-L1 immunotherapy in patients with SCLC. Moreover, using preclinical models, we demonstrated that γδ T cells are effective at tarlatamab (delta-like ligand 3 [DLL3]-CD3 bispecific T cell engager [BiTE])-redirected SCLC killing and that zoledronate, an FDA-approved compound, can sensitize SCLC cells to γδ T cell-mediated killing. Thus, our findings suggest that engaged γδ T cells are potentially valuable targets for SCLC therapy.

Author Info: (1) ACRF Cancer Biology and Stem Cells Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, The Univers

Author Info: (1) ACRF Cancer Biology and Stem Cells Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, VIC 3010, Australia. Electronic address: ng.ji@wehi.edu.au. (2) Department of Medical Biology, The University of Melbourne, Parkville, VIC 3010, Australia; Genetics and Gene Regulation Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia. (3) Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, VIC 3010, Australia. (4) ACRF Cancer Biology and Stem Cells Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, VIC 3010, Australia. (5) ACRF Cancer Biology and Stem Cells Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, VIC 3010, Australia. (6) Collaborative Centre for Genomic Cancer Medicine, The University of Melbourne, Parkville, VIC 3010, Australia; Department of Clinical Pathology, The University of Melbourne, Parkville, VIC 3010, Australia. (7) Department of Translational Genomics, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931 Cologne, Germany; Institute of Pathology, Faculty of Medicine and University of Hospital Cologne, University of Cologne, 50931 Cologne, Germany. (8) Department of Medical Biology, The University of Melbourne, Parkville, VIC 3010, Australia; Blood Cells and Blood Cancer Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia. (9) Clinical Translation, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; School of Medicine, Adelaide University, Adelaide, SA 5000, Australia; Department of Clinical Neuroscience, Karolinska Institute, 171 77 Stockholm, Sweden; Centre for Health Services Research, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia. (10) Department of Microbiology and Immunology, Columbia University Irving Medical Center, New York, NY 10032, USA. (11) Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, VIC 3010, Australia. (12) Centre for Inflammation Biology and Cancer Immunology, King's College London, London SE1 9RT, UK; Department of Medical Oncology, Guy's Hospital, London SE1 9RT, UK. (13) Collaborative Centre for Genomic Cancer Medicine, The University of Melbourne, Parkville, VIC 3010, Australia; Department of Clinical Pathology, The University of Melbourne, Parkville, VIC 3010, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC 3010, Australia. (14) WEHI Advanced Genomics Facility and Single Cell Open Research Endeavour (SCORE), Advanced Technology and Biology Division, Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia. (15) WEHI Advanced Genomics Facility and Single Cell Open Research Endeavour (SCORE), Advanced Technology and Biology Division, Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia. (16) Department of Medical Biology, The University of Melbourne, Parkville, VIC 3010, Australia; Immunology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia. (17) WEHI Advanced Genomics Facility and Single Cell Open Research Endeavour (SCORE), Advanced Technology and Biology Division, Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia. (18) ACRF Cancer Biology and Stem Cells Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia. (19) Department of Respiratory Medicine, Austin Health, Heidelberg, VIC 3084, Australia; Olivia Newton-John Cancer Research Institute, Heidelberg, VIC 3084, Australia; Department of Medicine, The University of Melbourne, Parkville, VIC 3010, Australia. (20) Department of Translational Genomics, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931 Cologne, Germany; Department of Otorhinolaryngology, Head and Neck Surgery, Faculty of Medicine and University Hospital Cologne, University Hospital of Cologne, 50931 Cologne, Germany. (21) Department of Medical Biology, The University of Melbourne, Parkville, VIC 3010, Australia; Genetics and Gene Regulation Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia. (22) Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, VIC 3010, Australia. (23) Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, VIC 3010, Australia. (24) Department of Medical Biology, The University of Melbourne, Parkville, VIC 3010, Australia; Genetics and Gene Regulation Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia. (25) Department of Medicine, The University of Melbourne, Parkville, VIC 3010, Australia; Department of Respiratory and Sleep Medicine, The Royal Melbourne Hospital, Parkville, VIC 3050, Australia. (26) ACRF Cancer Biology and Stem Cells Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, VIC 3010, Australia. Electronic address: sutherland.k@wehi.edu.au.

Citation: Cancer Cell 2026 Sep 18 Epub09/18/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42759517

Tags:
Close Modal

Subscribe to our mailing list

GDPR Marketing Permissions

The Fritsch Foundation/ACIR.org will use the information you provide on this form to be in touch with you and to send you a weekly digest on cance immunotherapy. Click below to confirm that you want to receive the weekly digest by:

You can change your mind at any time by clicking the unsubscribe link in the footer of any email you receive from us, or by contacting us at contact@acir.org. We will treat your information with respect and will never share it with any third-parties. By clicking below, you agree that we may process your information in accordance with these terms.

We use Mailchimp as our marketing platform. By clicking below to subscribe, you acknowledge that your information will be transferred to Mailchimp for processing. Learn more about Mailchimp's privacy practices here.

Close Modal

Small change for you. Big change for us!

This Thanksgiving season, show your support for cancer research by donating your change.

In less than a minute, link your credit card with our partner RoundUp App.

Every purchase you make with that card will be rounded up and the change will be donated to ACIR.

All transactions are securely made through Stripe.