Journal Articles

SYS6010, epidermal growth factor receptor-targeting antibody-drug conjugate for advanced non-small cell lung cancer: A phase 1 trial

(1) Li ZM (2) Zhou Z (3) He ZY (4) Han L (5) Fang J (6) Sun HM (7) Liu HF (8) Wang MX (9) Liu YB (10) Qu XJ (11) Yao Y (12) Gong Y (13) Yu Y (14) Shi HQ (15) Wang Y (16) Su CX (17) Yang KY (18) Shang YH (19) Ruan J (20) Yuan XL (21) Zhang MJ (22) Luo H (23) Cui JW (24) Lin XY (25) Li MX (26) Lou HZ (27) Yang RX (28) Wu H (29) Wang XC (30) Dan M (31) Zhang LQ (32) Su YZ (33) Wan XC (34) Zou K (35) Yang YY (36) Lu S

Cancer cell

In a phase 1 trial, Li and Zhou et al. evaluated the EGFR-targeting, topoisomerase I inhibitor JS-1-carrying ADC SYS6010 in 236 patients with previously treated, advanced NSCLC (diverse subtypes and EGFR status). One dose-limiting toxicity was observed (thrombocytopenia), and a recommended phase 2 dose was established. Treatment-related adverse events of all grades and grade ≥3 (mainly hematological) occurred in 99.6% and 57.2% of patients, respectively. Encouraging clinical activity was observed across disease types, irrespective of EGFR mutation status, and correlated with EGFR expression levels.

Contributed by Ute Burkhardt

(1) Li ZM (2) Zhou Z (3) He ZY (4) Han L (5) Fang J (6) Sun HM (7) Liu HF (8) Wang MX (9) Liu YB (10) Qu XJ (11) Yao Y (12) Gong Y (13) Yu Y (14) Shi HQ (15) Wang Y (16) Su CX (17) Yang KY (18) Shang YH (19) Ruan J (20) Yuan XL (21) Zhang MJ (22) Luo H (23) Cui JW (24) Lin XY (25) Li MX (26) Lou HZ (27) Yang RX (28) Wu H (29) Wang XC (30) Dan M (31) Zhang LQ (32) Su YZ (33) Wan XC (34) Zou K (35) Yang YY (36) Lu S

Cancer cell

In a phase 1 trial, Li and Zhou et al. evaluated the EGFR-targeting, topoisomerase I inhibitor JS-1-carrying ADC SYS6010 in 236 patients with previously treated, advanced NSCLC (diverse subtypes and EGFR status). One dose-limiting toxicity was observed (thrombocytopenia), and a recommended phase 2 dose was established. Treatment-related adverse events of all grades and grade ≥3 (mainly hematological) occurred in 99.6% and 57.2% of patients, respectively. Encouraging clinical activity was observed across disease types, irrespective of EGFR mutation status, and correlated with EGFR expression levels.

Contributed by Ute Burkhardt

ABSTRACT: SYS6010 is an antibody-drug conjugate targeting epidermal growth factor receptor (EGFR). We report the results of a phase 1 trial (ChiCTR2300072141) of SYS6010 in patients with non-small cell lung cancer (NSCLC). A total of 236 patients were treated. One dose-limiting toxicity occurred at 6.4 mg/kg; therefore, 4.2, 4.5, and 4.8 mg/kg were selected for cohort expansion. Treatment-related adverse events (TRAEs; any/grade ³ 3) occurred in 99.6%/57.2% of patients. Common grade ³3 TRAEs included neutropenia (30.9%), leukopenia (25.0%), and thrombocytopenia (17.4%). Objective response rate was 34.7% in EGFR-mutant NSCLC treated with EGFR tyrosine kinase inhibitors (TKIs) and platinum chemotherapy, 45.7% in EGFR-mutant NSCLC treated with EGFR TKIs, 20.0% in EGFR wild-type squamous NSCLC, and 35.7% in EGFR wild-type non-squamous NSCLC. Median progression-free survival and overall survival were 7.6 and 19.4 months, respectively, in EGFR-mutant NSCLC treated with EGFR TKIs and platinum chemotherapy. Overall, SYS6010 shows a manageable safety profile and encouraging antitumor activity in previously treated, advanced NSCLC.

Author Info: (1) Department of Medical Oncology, Shanghai Chest Hospital, Shanghai Jiaotong University, School of Medicine, Shanghai Key Laboratory of Thoracic Tumor Biotherapy, Shanghai 200030

Author Info: (1) Department of Medical Oncology, Shanghai Chest Hospital, Shanghai Jiaotong University, School of Medicine, Shanghai Key Laboratory of Thoracic Tumor Biotherapy, Shanghai 200030, P.R. China. (2) Department of Medical Oncology, Shanghai Chest Hospital, Shanghai Jiaotong University, School of Medicine, Shanghai Key Laboratory of Thoracic Tumor Biotherapy, Shanghai 200030, P.R. China. (3) Department of Thoracic Oncology, Fujian Provincial Cancer Hospital, Fuzhou 350014, P.R. China. (4) Department of Oncology, Xuzhou Center Hospital, Xuzhou 221000, P.R. China. (5) Department of Thoracic Oncology II, Beijing Cancer Hospital, Beijing 100142, P.R. China. (6) Department of Medical Oncology, Jiamusi Tumor Hospital, Jiamusi 154000 P.R. China. (7) Department of Critical Care Medicine, Jilin Cancer Hospital, Changchun 130000 P.R. China. (8) Clinical Pharmacology and Medical Department, The Fourth Hospital of Hebei Medical University, Shijiazhuang 050000, P.R. China. (9) Department of Medical Oncology, The Fourth Hospital of Hebei Medical University, Shijiazhuang 050000, P.R. China. (10) Department of Medical Oncology, The First Affiliated Hospital of China Medical University, Shenyang 110000, P.R. China. (11) Department of Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, P.R. China. (12) Phase I Ward, Chongqing University Cancer Hospital, Chongqing 400030, P.R. China. (13) Respiratory Medicine Ward 3, Cancer Hospital Affiliated to Harbin Medical University, Harbin 150000, P.R. China. (14) Department of Oncology, First Affiliated Hospital of Gannan Medical University, Ganzhou 341001, P.R. China. (15) Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, P.R. China. (16) Continuity of Care Unit, Shanghai Pulmonary Hospital, Shanghai 200433, P.R. China. (17) Department of Oro-maxillofacial Head and Neck Oncology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430048, P.R. China. (18) Department of Medical Oncology, Affiliated Hospital of Hebei University, Baoding 071000, P.R. China. (19) Department of Medical Oncology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, P.R. China. (20) Department of Medical Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, P.R. China. (21) Department of Oncology, The Second Affiliated Hospital of Anhui Medical University, Hefei 230601, P.R. China. (22) Department of Thoracic Tumor Radiotherapy, Jiangxi Cancer Hospital, Nanchang 330029 P.R. China. (23) Department of Oncology, The First Hospital of Jilin University, Changchun 130021, P.R. China. (24) Department of Medical Oncology, Fujian Medical University Union Hospital, Fuzhou 350001, P.R. China. (25) Department of Oncology, Army Medical Center with Distinctive Features, Chongqing, 400010, P.R. China. (26) Department of Oncology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310000, P.R. China. (27) Department of Internal Medicine No.2, Yunnan Cancer Hospital, Kunming 650106, P.R. China. (28) Department of Oncology, The First Affiliated Hospital with Nanjing Medical University, Nanjing 210029, P.R. China. (29) Department of Oncology, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou 510080, P.R. China. (30) Preclinical Division, CSPC Pharmaceutical Group Co., Ltd, Shijiazhuang 050035, P.R. China. (31) Clinical Development Division, CSPC Pharmaceutical Group Co., Ltd, Shijiazhuang 050035, P.R. China. (32) Clinical Development Division, CSPC Pharmaceutical Group Co., Ltd, Shijiazhuang 050035, P.R. China. (33) Clinical Development Division, CSPC Pharmaceutical Group Co., Ltd, Shijiazhuang 050035, P.R. China. (34) Clinical Development Division, CSPC Pharmaceutical Group Co., Ltd, Shijiazhuang 050035, P.R. China. (35) Clinical Development Division, CSPC Pharmaceutical Group Co., Ltd, Shijiazhuang 050035, P.R. China. (36) Department of Medical Oncology, Shanghai Chest Hospital, Shanghai Jiaotong University, School of Medicine, Shanghai Key Laboratory of Thoracic Tumor Biotherapy, Shanghai 200030, P.R. China. Electronic address: shunlu@sjtu.edu.cn.

Citation: Cancer Cell 2026 Aug 13 Epub08/13/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42594871

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UV irradiation drives lineage-specific MITF-mediated transcription of PD-L1 to confer immune tolerance to UV-mutated melanocytes

(1) Lo JA (2) Rachmin I (3) Flesher JL (4) Wu X (5) Kawakami A (6) Hejna M (7) Boozer JR (8) Nguyen N (9) King AD (10) Ji Y (11) Germana S (12) Kemeny LV (13) van der Sande AAJ (14) Cheng JB (15) Lotem M (16) Utne TR (17) Zhan Y (18) Roider EM (19) Mujahid N (20) Byrne EH (21) Singh S (22) Saidani M (23) Martineau S (24) Holic N (25) Baldeschi C (26) Martinat C (27) Freeman GJ (28) Hacohen N (29) Flaherty KT (30) Boland GM (31) Song JS (32) Sharpe AH (33) Demehri S (34) Yee C (35) Allouche J (36) Fisher DE

Immunity

Lo et al. found that in melanocytes, MITF mediates upregulation of PD-L1 by binding to an enhancer, inducing high baseline PD-L1 that is further upregulated upon exposure to UVR. This mechanism has a tolerogenic effect, protecting melanocytes from immune-mediated elimination, even after the accumulation of UV-induced mutations. While this mechanism did not appear to play a major role in immune-hot melanomas with high IFNγ expression, it did show an effect in less infiltrated melanomas, and could contribute to their development.

(1) Lo JA (2) Rachmin I (3) Flesher JL (4) Wu X (5) Kawakami A (6) Hejna M (7) Boozer JR (8) Nguyen N (9) King AD (10) Ji Y (11) Germana S (12) Kemeny LV (13) van der Sande AAJ (14) Cheng JB (15) Lotem M (16) Utne TR (17) Zhan Y (18) Roider EM (19) Mujahid N (20) Byrne EH (21) Singh S (22) Saidani M (23) Martineau S (24) Holic N (25) Baldeschi C (26) Martinat C (27) Freeman GJ (28) Hacohen N (29) Flaherty KT (30) Boland GM (31) Song JS (32) Sharpe AH (33) Demehri S (34) Yee C (35) Allouche J (36) Fisher DE

Immunity

Lo et al. found that in melanocytes, MITF mediates upregulation of PD-L1 by binding to an enhancer, inducing high baseline PD-L1 that is further upregulated upon exposure to UVR. This mechanism has a tolerogenic effect, protecting melanocytes from immune-mediated elimination, even after the accumulation of UV-induced mutations. While this mechanism did not appear to play a major role in immune-hot melanomas with high IFNγ expression, it did show an effect in less infiltrated melanomas, and could contribute to their development.

ABSTRACT: UV radiation (UVR) drives high mutational burdens, yet precursor melanocytes accumulate these mutations without triggering immune clearance. Here, we investigated whether melanocyte-intrinsic transcriptional program(s) underlie immune tolerance to mutations resulting from UVR exposure. In primary human melanocytes, expression of PD-L1 (CD274) was dependent on microphthalmia-associated transcription factor (MITF), a crucial regulator of melanocyte development and an intermediate in the UV-tanning pathway. MITF directly activated PD-L1 transcription by binding a conserved upstream enhancer containing functional E-box elements. MITF determined both baseline melanocytic PD-L1 expression in healthy skin and its induction following UVR, independent of interferon signaling. Melanocyte-restricted Pd-l1 deletion in mice triggered CD8(+) T cell infiltration and depigmentation after long-term UVB exposure, recapitulating features of human vitiligo. PD-L1-deficient human induced pluripotent stem cell (iPSC)-derived melanocytes underwent increased apoptosis and were more susceptible than PD-L1-intact melanocytes to gp100-specific CD8(+) T cell killing. Thus, a melanocyte-intrinsic MITF-PD-L1 tolerance program protects melanocytes from autoimmune destruction, potentially facilitating early immune evasion during melanoma development and conversely underlying the responsiveness of melanoma to PD-1/PD-L1 blockade.

Author Info: (1) Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129, USA; Department of Dermatology, Beth

Author Info: (1) Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129, USA; Department of Dermatology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. (2) Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129, USA. (3) Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129, USA. (4) Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129, USA. (5) Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129, USA; Department of Dermatology, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto 606-8507, Japan. (6) Department of Physics, University of Illinois Urbana-Champaign, Urbana, IL 61801, USA. (7) Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129, USA. (8) Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129, USA. (9) Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129, USA. (10) Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129, USA; Department of Stomatology, Central Hospital Affiliated to Shandong First Medical University, Jinan 250013, Shandong, China. (11) Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129, USA. (12) Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129, USA; HCEMM-SU Translational Dermatology Research Group, Semmelweis University, Budapest 1085, Hungary; Department of Physiology, Faculty of Medicine, Semmelweis University, Budapest 1094, Hungary; Department of Dermatology, Venereology and Dermatooncology, Faculty of Medicine, Semmelweis University, Budapest 1085, Hungary; MTA-SE LendŸlet "Momentum" Dermatology Research Group, Hungarian Academy of Sciences and Semmelweis University, Budapest 1085, Hungary. (13) Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129, USA. (14) Department of Dermatology, University of California, San Francisco, San Francisco, CA 94143, USA; Dermatology Service, San Francisco Veterans Administration Health Care System, San Francisco, CA 94121, USA. (15) Lautenberg Center for Immunology and Cancer Research, The Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem 91120, Israel; Center for Melanoma and Cancer Immunotherapy, Sharett Institute of Oncology, Jerusalem 91120, Israel; Hadassah Cancer Research Institute, Hadassah Hebrew University Medical Center, Jerusalem 91120, Israel. (16) Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129, USA. (17) Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129, USA. (18) Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129, USA; Department of Dermatology, University Hospital of Basel, 4031 Basel, Switzerland. (19) Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129, USA; Department of Dermatology, University of Utah, Salt Lake City, UT 84132, USA. (20) Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129, USA. (21) Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. (22) IStem, CECS, Corbeil-Essonnes 91100, France. (23) UniversitŽ Paris-Saclay, UniversitŽ d'Evry, Inserm, IStem, UMR861, Corbeil-Essonnes 91100, France. (24) UniversitŽ Paris-Saclay, UniversitŽ d'Evry, Inserm, IStem, UMR861, Corbeil-Essonnes 91100, France. (25) UniversitŽ Paris-Saclay, UniversitŽ d'Evry, Inserm, IStem, UMR861, Corbeil-Essonnes 91100, France. (26) UniversitŽ Paris-Saclay, UniversitŽ d'Evry, Inserm, IStem, UMR861, Corbeil-Essonnes 91100, France. (27) Department of Medical Oncology, Dana-Farber Cancer Institute, Department of Medicine, Harvard Medical School, Boston, MA 02215, USA. (28) Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Center for Cancer Research, Massachusetts General Hospital, Boston, MA 02142, USA. (29) Mass General Brigham Cancer Institute, Boston, MA 02114, USA. (30) Department of Surgery, Massachusetts General Hospital, Boston, MA 02114, USA; Krantz Family Center for Cancer Research, Massachusetts General Hospital, Boston, MA 02114, USA. (31) Department of Physics, University of Illinois Urbana-Champaign, Urbana, IL 61801, USA. (32) Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA; Gene Lay Institute of Immunology and Inflammation of Brigham and Women's Hospital, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02115, USA. (33) Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129, USA. (34) Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Parker Institute of Cancer Immunotherapy, San Francisco, CA 94129, USA. (35) Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129, USA; UniversitŽ Paris-Saclay, UniversitŽ d'Evry, Inserm, IStem, UMR861, Corbeil-Essonnes 91100, France. Electronic address: jeallouche@gmail.com. (36) Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129, USA. Electronic address: dfisher3@mgh.harvard.edu.

Citation: Immunity 2026 Aug 13 Epub08/13/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42594873

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Coordinated immune activation following KRAS inhibition in syngeneic models reveals molecular pathways that potentiate and limit antitumor immunity

(1) Lu DR (2) Osgood T (3) Ma S (4) Zhang H (5) Kanke M (6) Tan JA (7) Paudel SN (8) Zhou H (9) Estrada J (10) Yamawaki T (11) Tarbell K (12) Rex K (13) DeVoss J (14) Martin S (15) Wang S (16) Canon J (17) Lipford JR (18) Coxon A (19) Li CM

Cancer immunology research

Lu et al. profiled the cellular changes after KRAS(G12C) and MEK inhibition, and demonstrated that these treatments drove distinct neoplastic cell fates and immune responses in a CT26 KRASG12C tumor model. KRAS(G12C)i induced a cDC1-driven mature cDC state via tumor, endothelial, and fibroblast signaling, increased CD8+ T cell clonal expansion, and promoted anti-inflammatory macrophage polarization, while MEKi induced limited clonal expansion and anti-inflammatory macrophages. KRAS(G12C)i plus anti-PD-1 expanded effector T cells and increased T cell clonal persistence, proinflammatory macrophage states, and mediators of antitumor immunity.

Contributed by Shishir Pant

(1) Lu DR (2) Osgood T (3) Ma S (4) Zhang H (5) Kanke M (6) Tan JA (7) Paudel SN (8) Zhou H (9) Estrada J (10) Yamawaki T (11) Tarbell K (12) Rex K (13) DeVoss J (14) Martin S (15) Wang S (16) Canon J (17) Lipford JR (18) Coxon A (19) Li CM

Cancer immunology research

Lu et al. profiled the cellular changes after KRAS(G12C) and MEK inhibition, and demonstrated that these treatments drove distinct neoplastic cell fates and immune responses in a CT26 KRASG12C tumor model. KRAS(G12C)i induced a cDC1-driven mature cDC state via tumor, endothelial, and fibroblast signaling, increased CD8+ T cell clonal expansion, and promoted anti-inflammatory macrophage polarization, while MEKi induced limited clonal expansion and anti-inflammatory macrophages. KRAS(G12C)i plus anti-PD-1 expanded effector T cells and increased T cell clonal persistence, proinflammatory macrophage states, and mediators of antitumor immunity.

Contributed by Shishir Pant

ABSTRACT: While mutant-specific KRAS inhibitors are approved to treat cancer, a deeper understanding of intratumoral changes driven specifically by KRAS inhibition is needed to maximize therapeutic responses. Here, we used single-cell RNA-seq, flow cytometry, and spatial transcriptomics to distinguish mechanisms of tumor control after KRASG12C inhibition (KRAS(G12C)i) or MEK inhibition (MEKi). Despite both inhibiting the MAPK pathway, KRAS(G12C)i and MEKi drive the adaptation of distinct neoplastic cell fates affecting metabolism and cell cycle regulation, and additive tumor suppression is observed after co-administration. KRAS(G12C)i results in the emergence of a specific, cDC1-driven mature conventional dendritic cell (cDC) state. Co-culture of treated neoplastic cells with cDC1s is sufficient to upregulate maturation markers such as CCR7, intercellular communication analyses suggest activation is augmented through non-immune mediators. Both KRAS(G12C)i and MEKi increase infiltration of cytotoxic T cells, but MEKi, which also targets non-malignant cells, is associated with a reduced capacity for T-cell proliferation and degranulation, consistent with distinct adaptive immune activation mechanisms. We observe that combination treatment of KRAS(G12C)i with anti-PD-1 immunotherapy further expands effector T-cell states, increases clonal persistence, and induces pro-inflammatory macrophages associated with higher overall survival that were largely absent after KRAS(G12C)i alone. Furthermore, combination treatment enhances intercellular communication networks among non-PD-1+ expressing cells that can perpetuate cDC activation. Our findings delineate distinct tumor and immune responses to KRAS and MEK inhibition and identify molecular features of the responding tumor microenvironment that may be leveraged to improve therapeutic efficacy.

Author Info: (1) Amgen Inc. South San Francisco, CA United States. (2) Amgen Inc. Thousand Oaks, CA United States. (3) Amgen Inc. South San Francisco, CA United States. (4) Amgen Inc. South San

Author Info: (1) Amgen Inc. South San Francisco, CA United States. (2) Amgen Inc. Thousand Oaks, CA United States. (3) Amgen Inc. South San Francisco, CA United States. (4) Amgen Inc. South San Francisco, CA United States. (5) Amgen (United States) South San Franciso United States. ROR: https://ror.org/03g03ge92 (6) Amgen (United States) South San Francisco, CA United States. ROR: https://ror.org/03g03ge92 (7) Amgen Inc. Thousand Oaks, CA United States. (8) Amgen (United States) South San Francisco, CA United States. ROR: https://ror.org/03g03ge92 (9) Amgen Inc. Thousand Oaks, CA United States. (10) Amgen Inc. South San Francisco, CA United States. (11) Amgen Inc. South San Francisco, CA United States. (12) Amgen Inc. Thousand Oaks, CA United States. (13) Amgen (United States) South San Francisco, CA United States. ROR: https://ror.org/03g03ge92 (14) Amgen Inc. South San Francisco, CA United States. (15) Amgen Inc. South San Francisco, CA United States. (16) Amgen Inc. Thousand Oaks, CA United States. (17) Amgen (United States) United States. ROR: https://ror.org/03g03ge92 (18) Amgen Inc. Thousand Oaks, CA United States. (19) Amgen (United States) South San Francisco, CA United States. ROR: https://ror.org/03g03ge92

Citation: Cancer Immunol Res 2026 Jul 3 Epub07/03/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42397029

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CAR T Cells Targeting O-Glycosylated Fibronectin Exhibit Potent Cytolytic Activity and Combine with Tumoral Toll-Like Receptor Agonism to Overcome Tumor Resistance

(1) King-Peoples TR (2) Keane JT (3) Lewis HS (4) Liu F (5) Brookens SK (6) Dagher OK (7) Parvathaneni K (8) Gardner BL (9) Ahmed A (10) Furth EE (11) Lal P (12) Posey AD

Cancer immunology research

King-Peoples et al. assessed the Tn-glycosylated IIICS domain of fibronectin (Tn-FN) as an ECM-derived CAR target, and generated FDC6-BBζ CAR T cells using the FDC6 mAb. FDC6-BBζ CAR T cells recognized and lysed PC3 targets in an antigen-dependent manner in vitro, and showed durable tumor control, increased intratumoral CD3+ infiltration, and reduced tumor-collagen overlap in NSG PC3 xenografts. FDC6-BBζ CAR-mediated in vitro cytotoxicity against PC3 was dependent on IFNγR1 signaling, but was Fas-independent. TLR2/6 or TLR4 agonists restored FDC6-BBζ killing of IFNγR1-deficient targets via caspase/NLRP3 inflammasome activity.

Contributed by Shishir Pant

(1) King-Peoples TR (2) Keane JT (3) Lewis HS (4) Liu F (5) Brookens SK (6) Dagher OK (7) Parvathaneni K (8) Gardner BL (9) Ahmed A (10) Furth EE (11) Lal P (12) Posey AD

Cancer immunology research

King-Peoples et al. assessed the Tn-glycosylated IIICS domain of fibronectin (Tn-FN) as an ECM-derived CAR target, and generated FDC6-BBζ CAR T cells using the FDC6 mAb. FDC6-BBζ CAR T cells recognized and lysed PC3 targets in an antigen-dependent manner in vitro, and showed durable tumor control, increased intratumoral CD3+ infiltration, and reduced tumor-collagen overlap in NSG PC3 xenografts. FDC6-BBζ CAR-mediated in vitro cytotoxicity against PC3 was dependent on IFNγR1 signaling, but was Fas-independent. TLR2/6 or TLR4 agonists restored FDC6-BBζ killing of IFNγR1-deficient targets via caspase/NLRP3 inflammasome activity.

Contributed by Shishir Pant

ABSTRACT: Tumors remodel extracellular matrix (ECM) and glycosylation, yielding epitopes with restricted or limited detectability in normal adult tissues. Here, we evaluated the O-glycosylated IIICS domain of fibronectin (Tn-FN) as a chimeric antigen receptor (CAR) T cell target. FDC6-BBζ CAR T cells recognizing Tn-FN were benchmarked against EDB-FN-targeted L19-BBζ and Tn-MUC1-targeted 5E5-BBζ. FDC6-BBζ mediated robust, antigen-dependent activation and cytotoxicity, outperforming L19-BBζ and matching 5E5-BBζ in vitro and in NSG xenografts of prostate cancer. FDC6-BBζ and 5E5-BBζ CAR T cells achieved durable tumor control with increased intratumoral CD3⁺ infiltration and reduced tumor-collagen overlap. Cytotoxicity required intact tumor interferon-γ (IFNγ) receptor 1; L19-BBζ further depended on Fas, whereas FDC6-BBζ and 5E5-BBζ were less Fas-dependent. Tumoral toll-like receptor (TLR) 2/6 or TLR4 agonism restored FDC6-BBζ killing of IFNγR1-deficient targets and induced broad inflammatory and stress-response programs. Pharmacologic perturbation implicated caspase-dependent mechanisms and a contribution from inflammasome-linked signaling, whereas ferroptosis blockade did not abrogate restored killing. These findings establish Tn-FN as a glycoform-restricted, ECM-derived CAR target and show that innate agonists can reprogram tumor state to overcome resistance from impaired IFNγ signaling.

Author Info: (1) University of Pennsylvania Philadelphia, PA United States. ROR: https://ror.org/00b30xv10 (2) University of Pennsylvania United States. ROR: https://ror.org/00b30xv10 (3) Unive

Author Info: (1) University of Pennsylvania Philadelphia, PA United States. ROR: https://ror.org/00b30xv10 (2) University of Pennsylvania United States. ROR: https://ror.org/00b30xv10 (3) University of Pennsylvania Philadelphia, Pennsylvania United States. ROR: https://ror.org/00b30xv10 (4) University of Pennsylvania Philadelphia, Pennsylvania United States. ROR: https://ror.org/00b30xv10 (5) University of Pennsylvania United States. ROR: https://ror.org/00b30xv10 (6) University of Pennsylvania United States. ROR: https://ror.org/00b30xv10 (7) University of Pennsylvania Philadelphia United States. ROR: https://ror.org/00b30xv10 (8) University of Pennsylvania United States. ROR: https://ror.org/00b30xv10 (9) University of Pennsylvania United States. ROR: https://ror.org/00b30xv10 (10) University of Pennsylvania Philadelphia, PA United States. ROR: https://ror.org/00b30xv10 (11) Hospital of the University of Pennsylvania Philadelphia, PA United States. ROR: https://ror.org/02917wp91 (12) University of Pennsylvania Philadelphia, PA United States. ROR: https://ror.org/00b30xv10

Citation: Cancer Immunol Res 2026 Jul 3 Epub07/03/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42397032

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Peripheral Th17 immune signature associates with excellent response to anti-PD1/anti-PD-L1 therapy across solid tumors

(1) Li HL (2) Charmsaz S (3) Kao C (4) Pazzi C (5) Brancati M (6) Leatherman JM (7) Zhao LX (8) Arif W (9) Lee RP (10) Hernandez J (11) Gross NE (12) Ellis C (13) Thoburn C (14) Ged Y (15) Hoffman-Censits J (16) Lipson EJ (17) Baretti M (18) Chandler GS (19) Mohindra R (20) Tang L (21) Bansal S (22) Guha A (23) Jaffee EM (24) Zabransky DJ (25) Ho WJ (26) Yarchoan M (27) Nakazawa M

Cancer immunology research

Li et al. performed a multiyear study, prospectively analyzing peripheral immune cells and plasma cytokines from 124 patients with advanced pan-solid tumors treated with anti-PD-L1 or anti-PD-1. 30 patients achieved CR or durable PR with PFS ≥1 year, and exhibited higher levels of Th17-associated cytokines (IL-17F, -21, -23) and lower IL-8 levels at baseline and early on treatment than lesser responders. The latter showed elevated on-treatment IL-6, decreased Th17 cells, expansion of exhausted-like Th17 cells with lower lymphoid trafficking markers during early treatment, and trended toward higher on-treatment neutrophil-to-lymphocyte ratios.

Contributed by Paula Hochman

(1) Li HL (2) Charmsaz S (3) Kao C (4) Pazzi C (5) Brancati M (6) Leatherman JM (7) Zhao LX (8) Arif W (9) Lee RP (10) Hernandez J (11) Gross NE (12) Ellis C (13) Thoburn C (14) Ged Y (15) Hoffman-Censits J (16) Lipson EJ (17) Baretti M (18) Chandler GS (19) Mohindra R (20) Tang L (21) Bansal S (22) Guha A (23) Jaffee EM (24) Zabransky DJ (25) Ho WJ (26) Yarchoan M (27) Nakazawa M

Cancer immunology research

Li et al. performed a multiyear study, prospectively analyzing peripheral immune cells and plasma cytokines from 124 patients with advanced pan-solid tumors treated with anti-PD-L1 or anti-PD-1. 30 patients achieved CR or durable PR with PFS ≥1 year, and exhibited higher levels of Th17-associated cytokines (IL-17F, -21, -23) and lower IL-8 levels at baseline and early on treatment than lesser responders. The latter showed elevated on-treatment IL-6, decreased Th17 cells, expansion of exhausted-like Th17 cells with lower lymphoid trafficking markers during early treatment, and trended toward higher on-treatment neutrophil-to-lymphocyte ratios.

Contributed by Paula Hochman

ABSTRACT: Immune checkpoint inhibitors (ICIs) have transformed cancer care, at times generating durable partial or even complete responses in advanced cancers. However, only a minority of patients experience these "excellent" responses. Thus, there is a need for novel biomarkers that can identify those with robust clinical benefit. To address this, we prospectively collected blood samples from 124 patients with advanced and/or metastatic pan-solid tumors treated as standard of care with anti-PD1 or anti-PDL1 alone or in combination with other agents. In this cohort, 30 of 124 (24.2%) patients were classified as excellent responders (ERs), defined as experiencing a complete response or a durable partial response with progression-free survival (PFS) ³ one year. Peripheral immune cells were analyzed by Cytometry by Time-of-Flight and cytokines were analyzed using a multiplex immunoassay. At baseline and early-on-treatment, ERs had elevated concentrations of Th17-associated cytokines, IL-17F, IL-21, and IL-23, and decreased IL-8 compared to non-ERs (p<0.05). Elevated on-treatment IL-6 was also associated with non-ERs (p<0.05). High baseline IL-17F and IL-23 were associated with superior PFS, and high baseline IL-8 with inferior overall survival (p<0.05). Non-ERs demonstrated decreased proportions of Th17 cells from baseline to early-on-treatment. Regression analysis of functional markers in non-ERs showed a proliferation of exhaustion-like Th17 cells (Ki67+TIGIT+) from baseline to early-on-treatment (p<0.01), which was not present in ERs. This study identifies the Th17 pathway as a potential correlate of excellent ICI response and represents a comprehensive exploration of peripheral immune signatures associated with durable ICI benefit.

Author Info: (1) Sidney Kimmel Comprehensive Cancer Center Baltimore, MD United States. (2) Johns Hopkins Medicine Baltimore, MD United States. (3) Johns Hopkins Medicine Baltimore, MD United S

Author Info: (1) Sidney Kimmel Comprehensive Cancer Center Baltimore, MD United States. (2) Johns Hopkins Medicine Baltimore, MD United States. (3) Johns Hopkins Medicine Baltimore, MD United States. (4) Sidney Kimmel Comprehensive Cancer Center United States. (5) Johns Hopkins Medicine Baltimore, MD United States. (6) Sidney Kimmel Comprehensive Cancer Center Baltimore, MD United States. (7) Sidney Kimmel Comprehensive Cancer Center United States. (8) Johns Hopkins University United States. (9) Johns Hopkins Medicine Baltimore, MD United States. (10) Johns Hopkins Sidney Kimmel Comprehensive Cancer Center Baltimore, MD United States. (11) Johns Hopkins Medicine Baltimore, Maryland United States. (12) Sidney Kimmel Comprehensive Cancer Center United States. (13) Johns Hopkins Medicine Baltimore, MD United States. (14) Johns Hopkins Medicine Baltimore United States. (15) Johns Hopkins Medicine Baltimore, MD United States. (16) Johns Hopkins Medicine BALTIMORE, MD United States. (17) Johns Hopkins Medicine Baltimore, MD United States. (18) Roche (Switzerland) Basel Switzerland. (19) Roche (Switzerland) Basel Switzerland. (20) Genentech South San Francisco, CA United States. (21) Genentech San Francisco, CA United States. (22) Genentech San Francisco, CA United States. (23) Johns Hopkins University Baltimore, MD United States. (24) Johns Hopkins Medicine Baltimore, MD United States. (25) Johns Hopkins University Baltimore, MD United States. (26) Johns Hopkins Medicine Baltimore, MD United States. (27) Johns Hopkins Medicine Baltimore, MD United States.

Citation: Cancer Immunol Res 2026 Jun 26 Epub06/26/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42360819

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Intracranial delivery of B7-H3-targeting CAR-T cells for recurrent glioblastoma: a phase 1 trial

(1) Zhang Y (2) Chi X (3) Feng R (4) Xian N (5) Huang N (6) Sun S (7) Zhao X (8) Zhang P (9) Liu K (10) Ma Y (11) Zhang Y (12) Zhang K (13) Wang S (14) Chen X (15) Zhang J (16) Huang W (17) Huang B (18) Su TT (19) Yeung J (20) He J (21) Chen L (22) Ji N (23) Huang G

Nature medicine

In a phase 1 trial, Zhang, Chi, and Feng et al. treated 15 patients with B7-H3+ recurrent GBM with local delivery (intra-cerebroventricular or tumor cavity) of autologous B7-H3 CAR T cells. Treatment was well tolerated and commonly resulted in low-grade CRS; 3 patients treated at higher dose levels experienced more severe CNS-related AEs. Most patients (57.1%) achieved SD or better, and 1 CR lasted beyond 1 year. CAR copy numbers and cytokine levels increased most significantly in cranial fluids relative to blood, and tended to be dose-related. Greater induction of IFNγ/CXCL9/CXCL10 was associated with longer OS (overall median 19.1mo).

Contributed by Alex Najibi

(1) Zhang Y (2) Chi X (3) Feng R (4) Xian N (5) Huang N (6) Sun S (7) Zhao X (8) Zhang P (9) Liu K (10) Ma Y (11) Zhang Y (12) Zhang K (13) Wang S (14) Chen X (15) Zhang J (16) Huang W (17) Huang B (18) Su TT (19) Yeung J (20) He J (21) Chen L (22) Ji N (23) Huang G

Nature medicine

In a phase 1 trial, Zhang, Chi, and Feng et al. treated 15 patients with B7-H3+ recurrent GBM with local delivery (intra-cerebroventricular or tumor cavity) of autologous B7-H3 CAR T cells. Treatment was well tolerated and commonly resulted in low-grade CRS; 3 patients treated at higher dose levels experienced more severe CNS-related AEs. Most patients (57.1%) achieved SD or better, and 1 CR lasted beyond 1 year. CAR copy numbers and cytokine levels increased most significantly in cranial fluids relative to blood, and tended to be dose-related. Greater induction of IFNγ/CXCL9/CXCL10 was associated with longer OS (overall median 19.1mo).

Contributed by Alex Najibi

ABSTRACT: Recurrent glioblastoma (rGBM) is a leading brain malignancy with few therapeutic options. Here we present the complete results of a phase 1 trial investigating the safety and efficacy of autologous B7-H3-targeting chimeric antigen receptor T (CAR-T) cell (TX103) therapy for the treatment of rGBM. In this open-label, 3 + 3 dose-escalation trial, patients aged 18-75 years with B7-H3-positive (≥30%) rGBM received intracranial infusion of TX103 at three dose levels (DLs-2 × 107, 6 × 107 and 1.5 × 108 cells per infusion). Primary endpoints were safety, maximum tolerated dose (MTD), and recommended phase 2 dose (RP2D). Secondary endpoints included survival, pharmacokinetics and immunological response. Fifteen patients received a total of 72 intracranial infusions and 13 underwent repeated infusions. TX103 therapy was well tolerated, with no dose-limiting toxicities or MTD identified. Treatment-related adverse events (TRAEs) included low-grade cytokine release syndrome (86.7%), sinus tachycardia (53.3%), vomiting (53.3%), hypertension (53.3%) and elevated intracranial pressure (46.7%). Three grade 3 TRAEs considered serious adverse events occurred (elevated intracranial pressure, epilepsy and depressed consciousness), two at DL3. The 12-month overall survival (OS) rate was 66.7% and median OS was 19.1 months (95% confidence interval = 8.93, not reached) from first infusion. Disease control (stable disease or better) was achieved in 8 of 14 patients with measurable disease, including one complete response sustained through the latest follow-up. Cerebrospinal fluid showed a marked increase in CAR gene copy numbers and cytokine release, with minimal peripheral activity and no cumulative toxicity after repeated infusions. In conclusion, intracranial TX103 infusion demonstrated acceptable safety and encouraging efficacy in rGBM, supporting a future phase 2 evaluation at the RP2D (DL2, 6 × 107 cells per infusion). ClinicalTrials.gov registration: NCT05241392 .

Author Info: (1) Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China. (2) Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical Univ

Author Info: (1) Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China. (2) Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China. (3) Tcelltech Biological Science and Technology, Fuzhou, China. (4) Tcelltech Biological Science and Technology, Fuzhou, China. Institute of Immunotherapy, Fujian Medical University, Fuzhou, China. (5) Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China. (6) Department of Radiology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China. Department of Neuroradiology, Beijing Neurosurgical Institute, Beijing, China. (7) Department of Nuclear Medicine, Beijing Tiantan Hospital, Capital Medical University, Beijing, China. (8) Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China. (9) Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China. (10) Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China. (11) Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China. (12) Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China. (13) Department of Radiology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China. (14) Tcelltech Biological Science and Technology, Fuzhou, China. (15) Tcelltech Biological Science and Technology, Fuzhou, China. (16) Department of Epidemiology and Health Statistics, School of Public Health, Fujian Medical University, Fuzhou, China. (17) Department of Immunobiology and Medicine (Medical Oncology), Yale University School of Medicine, New Haven, CT, USA. (18) Department of Immunobiology and Medicine (Medical Oncology), Yale University School of Medicine, New Haven, CT, USA. (19) Department of Immunobiology and Medicine (Medical Oncology), Yale University School of Medicine, New Haven, CT, USA. Department of Neurosurgery, Yale University School of Medicine, New Haven, CT, USA. (20) Department of Immunobiology and Medicine (Medical Oncology), Yale University School of Medicine, New Haven, CT, USA. (21) Department of Immunobiology and Medicine (Medical Oncology), Yale University School of Medicine, New Haven, CT, USA. lieping.chen@yale.edu. (22) Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China. jinan@mail.ccmu.edu.cn. (23) Tcelltech Biological Science and Technology, Fuzhou, China. ghuang@tcelltech.com. Institute of Immunotherapy, Fujian Medical University, Fuzhou, China. ghuang@tcelltech.com.

Citation: Nat Med 2026 Aug 6 Epub08/06/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42562965

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Fc-optimized GITR antibody enhances a CD4 T cell-dendritic cell crosstalk to promote antitumor immunity

(1) Avraham Y (2) Barth N (3) Yair Bar-On T (4) Toval B (5) Habshush Menachem A (6) Blanga J (7) Herzog E (8) Rotem H (9) Shapir Itai Y (10) Feferman T (11) Biton M (12) Dahan R

Nature cancer

Avraham and Barth et al. focused on optimizing the therapeutic potential of agonistic anti-GITR mAbs. Fc-engineered versions of human anti-GITR mAbs were evaluated in humanized FcγR mice. The Fc variant GA-aFuc (enhanced binding to hFcγRIIa and hFcγRIIIa, but not to inhibitory hFcγRIIb) outperformed other IgG scaffolds in tumor models via multiple FcγR-mediated pathways, and was less reliant on GITR agonism. These included selective Treg depletion in the TIME and increased CD4+ T cell and dendritic cell engagement and activation, resulting in cytotoxic Foxp3-CD4+ T cell activation and enhanced CD8+ T cell activity.

Contributed by Katherine Turner

(1) Avraham Y (2) Barth N (3) Yair Bar-On T (4) Toval B (5) Habshush Menachem A (6) Blanga J (7) Herzog E (8) Rotem H (9) Shapir Itai Y (10) Feferman T (11) Biton M (12) Dahan R

Nature cancer

Avraham and Barth et al. focused on optimizing the therapeutic potential of agonistic anti-GITR mAbs. Fc-engineered versions of human anti-GITR mAbs were evaluated in humanized FcγR mice. The Fc variant GA-aFuc (enhanced binding to hFcγRIIa and hFcγRIIIa, but not to inhibitory hFcγRIIb) outperformed other IgG scaffolds in tumor models via multiple FcγR-mediated pathways, and was less reliant on GITR agonism. These included selective Treg depletion in the TIME and increased CD4+ T cell and dendritic cell engagement and activation, resulting in cytotoxic Foxp3-CD4+ T cell activation and enhanced CD8+ T cell activity.

Contributed by Katherine Turner

ABSTRACT: Targeting the stimulatory immune checkpoint glucocorticoid-induced TNFR-related protein (GITR) using agonistic monoclonal antibodies (mAbs) is a promising strategy for cancer immunotherapy that activates effector T cells and eliminates regulatory T cells. The antitumor activity of anti-GITR mAbs depends on the engagement of the fragment crystallizable (Fc) domain to their receptors (FcγRs); however, this has not been comprehensively investigated in human anti-GITR mAbs. Here, we used Fc protein and glycan engineering to modify the FcγR interactions of anti-GITR human mAbs and characterized them in humanized mice. We identified an Fc-optimized human IgG scaffold that enhances antitumor efficacy through multiple FcγR-mediated mechanisms, including regulatory T cell depletion and mutual engagement and activation of CD4+ T cells and dendritic cells, leading to antitumor cytotoxicity of CD4+ T cells and enhanced CD8+ T cell activity. Our findings suggest a strategy to optimize human anti-GITR mAbs, harnessing beneficial immune pathways to improve their therapeutic potential.

Author Info: (1) Department of Systems Immunology, Weizmann Institute of Science, Rehovot, Israel. (2) Department of Systems Immunology, Weizmann Institute of Science, Rehovot, Israel. (3) Depa

Author Info: (1) Department of Systems Immunology, Weizmann Institute of Science, Rehovot, Israel. (2) Department of Systems Immunology, Weizmann Institute of Science, Rehovot, Israel. (3) Department of Systems Immunology, Weizmann Institute of Science, Rehovot, Israel. (4) Department of Systems Immunology, Weizmann Institute of Science, Rehovot, Israel. (5) Department of Immunology and Regenerative Biology, Weizmann Institute of Science, Rehovot, Israel. (6) Department of Systems Immunology, Weizmann Institute of Science, Rehovot, Israel. (7) Department of Systems Immunology, Weizmann Institute of Science, Rehovot, Israel. (8) Department of Systems Immunology, Weizmann Institute of Science, Rehovot, Israel. (9) Department of Systems Immunology, Weizmann Institute of Science, Rehovot, Israel. (10) Department of Systems Immunology, Weizmann Institute of Science, Rehovot, Israel. (11) Department of Immunology and Regenerative Biology, Weizmann Institute of Science, Rehovot, Israel. (12) Department of Systems Immunology, Weizmann Institute of Science, Rehovot, Israel. rony.dahan@weizmann.ac.il.

Citation: Nat Cancer 2026 Aug 5 Epub08/05/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42557403

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Oncogenic Kras targeting with MRTX1133 or Daraxonrasib specifically synergize with anti-CTLA4 to promote anti-tumor immunity in pancreatic cancer

Spotlight 

Krishnan K. Mahadevan (1), Ana S. Maldonado (1), Bingrui Li (1), Aaron A. Bickert (1), Adrian Kacperczyk-Perdyan (1,2), Shreyasee V. Kumbhar (1), Sujan Piya (3), Amari M. Sockwell (1), Sami J. Morse (1), Kent Arian (1), Hikaru Sugimoto (1), Shabnam Shalapour (1), David S. Hong (4), Timothy P. Heffernan (5), Anirban Maitra (3)& Raghu Kalluri (1,6,7,8)

Nature communications

To overcome PDAC resistance to Kras* targeting using MRTX1133 or daraxonrasib, which enhances infiltration T cells, including various CD8+ T cell, CD4+ conventional T cell, and Treg phenotypes, Mahadevan et al. found that the addition of anti-CTLA-4 (but not other ICB) synergized by further increasing TILs, reprogramming Tregs to a more naive (less suppressive) phenotype, reversing exhaustion in CD8+ T cells, and promoting the formation of TLSs, together resulting in better PDAC suppression and longer survival. Treg reprogramming occurred through epigenetic downregulation of AP-1 transcription factors in the IL-10 and IL-35 promoter regions.

Contributed by Lauren Hitchings

Krishnan K. Mahadevan (1), Ana S. Maldonado (1), Bingrui Li (1), Aaron A. Bickert (1), Adrian Kacperczyk-Perdyan (1,2), Shreyasee V. Kumbhar (1), Sujan Piya (3), Amari M. Sockwell (1), Sami J. Morse (1), Kent Arian (1), Hikaru Sugimoto (1), Shabnam Shalapour (1), David S. Hong (4), Timothy P. Heffernan (5), Anirban Maitra (3)& Raghu Kalluri (1,6,7,8)

Nature communications

To overcome PDAC resistance to Kras* targeting using MRTX1133 or daraxonrasib, which enhances infiltration T cells, including various CD8+ T cell, CD4+ conventional T cell, and Treg phenotypes, Mahadevan et al. found that the addition of anti-CTLA-4 (but not other ICB) synergized by further increasing TILs, reprogramming Tregs to a more naive (less suppressive) phenotype, reversing exhaustion in CD8+ T cells, and promoting the formation of TLSs, together resulting in better PDAC suppression and longer survival. Treg reprogramming occurred through epigenetic downregulation of AP-1 transcription factors in the IL-10 and IL-35 promoter regions.

Contributed by Lauren Hitchings

ABSTRACT: Lack of sustained response to oncogenic Kras (Kras*) inhibition in pancreatic ductal adenocarcinoma (PDAC) underscores the need to identify effective combination therapies. Here, we demonstrate that Kras* targeting using MRTX1133 or Daraxonrasib recruits diverse T-cell infiltrates, including regulatory (Tregs), effector and exhausted T cells into the PDAC microenvironment. Kras* inhibition induces T-cell influx and offers a therapeutic window to specifically prime PDAC to anti-CTLA4 immune checkpoint blockade efficacy, in contrast to anti-PD1, anti-Tim3, anti-Lag3, anti-Vista, and anti-4-1BB agonist combination therapy. Mechanistically, anti-CTLA4 combination therapy transcriptionally reprograms effector Tregs to a naive phenotype, reverses CD8+ T-cell exhaustion, and promotes recruitment of functional tertiary lymphoid structures to mediate anti-tumor immunity. Single-cell ATAC sequencing reveals that Treg reprogramming by anti-CTLA4 is epigenetically regulated by downregulation of AP-1 family transcription factors in the IL-35 promoter region. This study reveals an actionable vulnerability in the adaptive immune response in Kras* targeted PDAC with immediate clinical implications.

Author Info: (1) Department of Cancer Biology, University of Texas MD Anderson Cancer Center, Houston, TX, USA (2) 3P-Medicine Laboratory, Medical University of Gdansk, 80-210 Gdansk, Poland (3

Author Info: (1) Department of Cancer Biology, University of Texas MD Anderson Cancer Center, Houston, TX, USA (2) 3P-Medicine Laboratory, Medical University of Gdansk, 80-210 Gdansk, Poland (3) Departments of Anatomical Pathology and Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, TX, USA (4) Department of Investigative Cancer Therapeutics, University of Texas MD Anderson Cancer Center, Houston, TX, USA (5) Institute for Applied Science and TRACTION platform, University of Texas MD Anderson Cancer Center, Houston, TX, USA (6) Department of Bioengineering, Rice University, Houston, TX, USA (7) Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA (8) Department of Pathology, University of Texas Medical Branch, Galveston, TX, USA

Citation: Nat com 2026

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The Dendritic Cell-based Vaccine PROTEXI leverages Antiviral CD4 T cell Memory to boost anti-tumor immune responses in mice Spotlight 

(1) Kang JM (2) Han EH (3) Choi JK (4) Youm S (5) Pareek T (6) Levi L (7) Kim SJ (8) Letterio J (9) Lim S

Nature communications | Free PMC Article

Kang and Han et al. developed PROTEXI, a vaccine platform comprising autologous DCs loaded with both tumor-specific CD8+ T and SARS-CoV-2 Spike protein CD4+ TH cell epitopes. In mouse tumor models, PROTEXI required both CD4+ and CD8+ T cells for efficacy and immune memory induction, and in ICI-resistant models, synergized with anti-PD-1 by revitalizing TEX cells. PROTEXI plus Vactosertib, a TGFβR inhibitor, activated “cold” TIMEs by driving T cell recruitment, cytotoxicity, and epitope spreading. PROTEXI was also efficacious in humanized mouse tumor models, dependent on pre-existing human CD4+ T cells against SARS-CoV-2 Spike epitopes.

Contributed by Paula Hochman

(1) Kang JM (2) Han EH (3) Choi JK (4) Youm S (5) Pareek T (6) Levi L (7) Kim SJ (8) Letterio J (9) Lim S

Nature communications | Free PMC Article

Kang and Han et al. developed PROTEXI, a vaccine platform comprising autologous DCs loaded with both tumor-specific CD8+ T and SARS-CoV-2 Spike protein CD4+ TH cell epitopes. In mouse tumor models, PROTEXI required both CD4+ and CD8+ T cells for efficacy and immune memory induction, and in ICI-resistant models, synergized with anti-PD-1 by revitalizing TEX cells. PROTEXI plus Vactosertib, a TGFβR inhibitor, activated “cold” TIMEs by driving T cell recruitment, cytotoxicity, and epitope spreading. PROTEXI was also efficacious in humanized mouse tumor models, dependent on pre-existing human CD4+ T cells against SARS-CoV-2 Spike epitopes.

Contributed by Paula Hochman

ABSTRACT: The efficacy of dendritic cell (DC) cancer vaccines is linked to poor immunogenicity of tumor-associated antigens and failure to elicit robust MHC class II-restricted CD4⁺ T-cell responses. Here, we introduce PROTEXI, a DC vaccine platform that optimizes tumor immunity by co-presenting tumor-specific CD8⁺ T-cell epitopes alongside CD4⁺ T helper epitopes from the SARS-CoV-2 Spike protein, leveraging widespread anti-viral immunity. In preclinical mouse models of melanoma and breast cancer, PROTEXI significantly reduces tumor growth and improves survival by promoting robust T cell infiltration into immune-cold tumors, increasing cytotoxic T cell responses via epitope spreading, and activating genes linked to optimal DC, NK cell, and T cell function. Furthermore, PROTEXI elicits superior responses when combined with other immunotherapy agents in models of therapy-resistant tumors. Finally, in a humanized mouse model of melanoma, PROTEXI vaccine co-presenting CD4⁺ T-specific Spike epitopes with CD8⁺ T cell-restricted PRAME and MAGE-A3 antigens, significantly reduces tumor burden. Thus, these data underscore the potential of harnessing pre-existing viral-specific immunity to enhance the efficacy of DC vaccines in immune-cold tumors.

Author Info: (1) The Angie Fowler Adolescent & Young Adult Cancer Institute, University Hospitals Rainbow Babies & Children's Hospital, Cleveland, OH, USA. Department of Pediatric Hematology &

Author Info: (1) The Angie Fowler Adolescent & Young Adult Cancer Institute, University Hospitals Rainbow Babies & Children's Hospital, Cleveland, OH, USA. Department of Pediatric Hematology & Oncology, University Hospitals Cleveland Medical Center, Cleveland, OH, USA. (2) Department of Pediatrics, Case Western Reserve University, Cleveland, OH, USA. (3) Celloram Inc., 11000 Cedar Avenue STE 100F #23, Cleveland, OH, USA. (4) Department of Pediatrics, Case Western Reserve University, Cleveland, OH, USA. (5) Celloram Inc., 11000 Cedar Avenue STE 100F #23, Cleveland, OH, USA. (6) Celloram Inc., 11000 Cedar Avenue STE 100F #23, Cleveland, OH, USA. (7) MedPacto Inc., 92, Myeongdal-ro, Seocho-gu, Seoul, Republic of Korea. (8) The Angie Fowler Adolescent & Young Adult Cancer Institute, University Hospitals Rainbow Babies & Children's Hospital, Cleveland, OH, USA. John.Letterio@UHHospitals.org. Department of Pediatric Hematology & Oncology, University Hospitals Cleveland Medical Center, Cleveland, OH, USA. John.Letterio@UHHospitals.org. Department of Pediatrics, Case Western Reserve University, Cleveland, OH, USA. John.Letterio@UHHospitals.org. The Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, OH, USA. John.Letterio@UHHospitals.org. (9) The Angie Fowler Adolescent & Young Adult Cancer Institute, University Hospitals Rainbow Babies & Children's Hospital, Cleveland, OH, USA. SeunghwanLim@Celloram.com. Celloram Inc., 11000 Cedar Avenue STE 100F #23, Cleveland, OH, USA. SeunghwanLim@Celloram.com.

Citation: Nat Commun 2026 Jul 27 17: Epub07/27/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42509244

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Tumor-induced dendritic cell deregulation perturbs T cell proliferation and predicts clinical outcome in acute lymphoblastic leukemia Spotlight 

(1) Kumar A (2) Hamane K (3) Duault C (4) Lima-Junior JR (5) Jung DH (6) Qin H (7) Salcido S (8) Huang M (9) Guo X (10) Taghi Khani A (11) Sanchez Ortiz A (12) Ghoda L (13) Marcucci G (14) Lacayo NJ (15) Sakamoto KM (16) Hurtz C (17) Carroll M (18) Tasian SK (19) Geng H (20) Ji L (21) Armenian S (22) Izraeli S (23) Wu X (24) Maecker HT (25) Swaminathan S

Cell reports. Medicine

Kumar et al. characterized the transcriptome and proteome of the DC compartment in both pediatric and adult ALL, and demonstrated that DC maturation into functional lineages was disrupted. Proliferation, antigen presentation, and cytokine production were impaired across all residual DC subsets, except progenitor/DC4 fractions, leading to a semi-mature, potentially tolerogenic phenotype with defective T cell priming. MYC overexpression in malignant lymphoblasts partly drove the disruption of DC homeostasis. A stimulated DC transcriptional signature at ALL diagnosis correlated with favorable outcomes in B-ALL, but adverse outcomes in T-ALL.

Contributed by Shishir Pant

(1) Kumar A (2) Hamane K (3) Duault C (4) Lima-Junior JR (5) Jung DH (6) Qin H (7) Salcido S (8) Huang M (9) Guo X (10) Taghi Khani A (11) Sanchez Ortiz A (12) Ghoda L (13) Marcucci G (14) Lacayo NJ (15) Sakamoto KM (16) Hurtz C (17) Carroll M (18) Tasian SK (19) Geng H (20) Ji L (21) Armenian S (22) Izraeli S (23) Wu X (24) Maecker HT (25) Swaminathan S

Cell reports. Medicine

Kumar et al. characterized the transcriptome and proteome of the DC compartment in both pediatric and adult ALL, and demonstrated that DC maturation into functional lineages was disrupted. Proliferation, antigen presentation, and cytokine production were impaired across all residual DC subsets, except progenitor/DC4 fractions, leading to a semi-mature, potentially tolerogenic phenotype with defective T cell priming. MYC overexpression in malignant lymphoblasts partly drove the disruption of DC homeostasis. A stimulated DC transcriptional signature at ALL diagnosis correlated with favorable outcomes in B-ALL, but adverse outcomes in T-ALL.

Contributed by Shishir Pant

ABSTRACT: Perturbations in dendritic cells (DCs) in B/T cell acute lymphoblastic leukemia (ALL), their cause(s) and consequence(s) on antileukemia immunity, and patient outcomes remain poorly explored. We find that maturation of DC1-6 subsets is disrupted in children and adults with ALL. Conventional DC1 and DC2 subpopulations are reduced at the expense of the progenitors and the DC4 fractions in ALL. The potential to mature, present antigens, and produce cytokines for initiating T cell surveillance appears to be impaired in every ALL DC subset. Such DC subsets are accordingly unable to induce T cell proliferation compared to DCs from healthy donors. MYC overexpression in ALL cells disrupts DC homeostasis and reduces the ability of DCs to induce T cell proliferation. Predominance of cells with transcriptional signatures typical of "stimulated DCs" predicts favorable clinical outcomes in B-ALL, while it is associated with unfavorable outcomes in T-ALL. Phenotyping DC subsets at ALL diagnosis could thus be valuable in informing treatment outcomes.

Author Info: (1) Department of Systems Biology, Beckman Research Institute of City of Hope, Monrovia, CA 91016, USA. (2) Department of Systems Biology, Beckman Research Institute of City of Hop

Author Info: (1) Department of Systems Biology, Beckman Research Institute of City of Hope, Monrovia, CA 91016, USA. (2) Department of Systems Biology, Beckman Research Institute of City of Hope, Monrovia, CA 91016, USA. (3) The Human Immune Monitoring Center (HIMC), Institute for Immunity, Transplantation and Infection, Stanford University School of Medicine, Stanford, CA 94305, USA. (4) Department of Systems Biology, Beckman Research Institute of City of Hope, Monrovia, CA 91016, USA. (5) Department of Systems Biology, Beckman Research Institute of City of Hope, Monrovia, CA 91016, USA. (6) Department of Molecular and Cellular Biology, City of Hope National Medical Center, Duarte, CA 91010, USA. (7) The Hematopoietic Tissue Biorepository/Research Pathology Shared Resources, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA. (8) Department of Pediatrics (Hematology and Oncology), Stanford University School of Medicine, Stanford, CA 94305, USA. (9) Department of Systems Biology, Beckman Research Institute of City of Hope, Monrovia, CA 91016, USA. (10) Department of Systems Biology, Beckman Research Institute of City of Hope, Monrovia, CA 91016, USA. (11) Department of Systems Biology, Beckman Research Institute of City of Hope, Monrovia, CA 91016, USA. (12) The Hematopoietic Tissue Biorepository/Research Pathology Shared Resources, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA. (13) The Hematopoietic Tissue Biorepository/Research Pathology Shared Resources, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA; The Department of Hematological Malignancies Translational Science, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA. (14) Department of Pediatrics (Hematology and Oncology), Stanford University School of Medicine, Stanford, CA 94305, USA. (15) Department of Pediatrics (Hematology and Oncology), Stanford University School of Medicine, Stanford, CA 94305, USA. (16) Department of Basic Science, Division of Cancer Sciences, Loma Linda University School of Medicine, Loma Linda, CA 92350, USA. (17) Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA. (18) Division of Oncology and Center for Childhood Cancer Research, Department of Pediatrics, Children's Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Department of Pediatrics and Abramson Cancer Center, University of Pennsylvania School of Medicine, Philadelphia, PA, USA. (19) Department of Laboratory Medicine, University of California, San Francisco, San Francisco, CA 94143, USA. (20) Department of Clinical Population and Public Health Sciences, University of Southern California, Los Angeles, CA 91016, USA. (21) Department of Pediatrics, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA. (22) Schneider Children's Medical Center, Tel Aviv University, Felsenstein Research Institute, Tel Aviv, Israel. (23) Department of Molecular and Cellular Biology, City of Hope National Medical Center, Duarte, CA 91010, USA. (24) The Human Immune Monitoring Center (HIMC), Institute for Immunity, Transplantation and Infection, Stanford University School of Medicine, Stanford, CA 94305, USA. (25) Department of Systems Biology, Beckman Research Institute of City of Hope, Monrovia, CA 91016, USA; Department of Pediatrics, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA; Center for RNA Biology and Therapeutics, Beckman Research Institute of City of Hope, Monrovia, CA 91016, USA. Electronic address: sswaminathan@coh.org.

Citation: Cell Rep Med 2026 Jul 28 102945 Epub07/28/2026

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/42520804

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