Journal Articles

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

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

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

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

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

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.

First-in-human testing of a mutant KRAS vaccine for pancreatic cancer interception in high-risk cohorts

In a phase 1 trial, Haldar, Huff, et al. treated 20 volunteers with high-risk of PDAC development (based on family history or genetics, plus radiographic indication of a precursor lesion/cyst) with a prophylactic SLP vaccine against 6 common KRAS mutations. The vaccine was well tolerated, and 90% of recipients developed mutant KRAS-specific T cell responses, although response rates varied against individual KRAS mutations. Polyfunctional, memory mKRAS-specific CD4+ and CD8+ T cells and novel clonotypes were detected and persisted 1-2 years after vaccination. No patients developed PDAC over a 16.5-month follow-up, and many had evidence of cyst regression or resolution.

Contributed by Alex Najibi

In a phase 1 trial, Haldar, Huff, et al. treated 20 volunteers with high-risk of PDAC development (based on family history or genetics, plus radiographic indication of a precursor lesion/cyst) with a prophylactic SLP vaccine against 6 common KRAS mutations. The vaccine was well tolerated, and 90% of recipients developed mutant KRAS-specific T cell responses, although response rates varied against individual KRAS mutations. Polyfunctional, memory mKRAS-specific CD4+ and CD8+ T cells and novel clonotypes were detected and persisted 1-2 years after vaccination. No patients developed PDAC over a 16.5-month follow-up, and many had evidence of cyst regression or resolution.

Contributed by Alex Najibi

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) arises from precursor lesions over a decade-plus, offering a window for interception in high-risk individuals, but current surveillance detects a minority of precursors. Mutant KRAS (mKRAS) is present in most PDACs and their precursors, making it an appealing target for immune-based interception. We conducted a phase I, first-in-human study of a peptide vaccine targeting six common KRAS mutations (mKRAS-VAX) in 20 individuals with hereditary PDAC predisposition and a radiographic pancreatic abnormality (NCT05013216) to assess safety, immunogenicity, and T cell persistence. Adverse events were grade 1-2. Vaccination elicited a significant mKRAS-specific T cell response in 18/20 participants (90%). Longitudinal TCR sequencing demonstrated persistence of vaccine-induced mKRAS-specific clonotypes for up to 2 years. Over a median follow-up of 16.5 months, no participants developed PDAC. These findings demonstrate that mKRAS-VAX is safe and generates durable T cell responses, which support the advancement of mKRAS-targeted vaccination for PDAC interception.

Author Info: (1) The University of Texas MD Anderson Cancer Center Houston, TX United States. ROR: https://ror.org/04twxam07 (2) Johns Hopkins Medicine Baltimore United States. ROR: https://ror

Author Info: (1) The University of Texas MD Anderson Cancer Center Houston, TX United States. ROR: https://ror.org/04twxam07 (2) Johns Hopkins Medicine Baltimore United States. ROR: https://ror.org/037zgn354 (3) Johns Hopkins Medicine Baltimore, Maryland United States. ROR: https://ror.org/037zgn354 (4) Johns Hopkins Medicine Baltimore, Maryland United States. ROR: https://ror.org/037zgn354 (5) Johns Hopkins Medicine Baltimore, MD United States. ROR: https://ror.org/037zgn354 (6) Johns Hopkins University United States. ROR: https://ror.org/00za53h95 (7) Johns Hopkins Medicine Baltimore, MD United States. ROR: https://ror.org/037zgn354 (8) Johns Hopkins School of Medicine Baltimore, MD United States. (9) Icahn School of Medicine at Mount Sinai New York United States. ROR: https://ror.org/04a9tmd77 (10) Johns Hopkins Medicine Baltimore, MD United States. ROR: https://ror.org/037zgn354 (11) Johns Hopkins Medicine Baltimore United States. ROR: https://ror.org/037zgn354 (12) The Johns Hopkins Medical Institutions Baltimore, MD United States. (13) Johns Hopkins University Baltimore, MD United States. ROR: https://ror.org/00za53h95 (14) Johns Hopkins University Baltimore, MD United States. ROR: https://ror.org/00za53h95 (15) Johns Hopkins Medicine Baltimore United States. ROR: https://ror.org/037zgn354 (16) Johns Hopkins University Baltimore, MD United States. ROR: https://ror.org/00za53h95 (17) Johns Hopkins University Baltimore, MD United States. ROR: https://ror.org/00za53h95 (18) Sidney Kimmel Comprehensive Cancer Center Baltimore, Maryland United States. ROR: https://ror.org/05m5b8x20 (19) Johns Hopkins Medicine Baltimore, MD United States. ROR: https://ror.org/037zgn354 (20) Johns Hopkins Medicine Baltimore, MD United States. ROR: https://ror.org/037zgn354 (21) Sidney Kimmel Comprehensive Cancer Center Baltimore, MD United States. ROR: https://ror.org/05m5b8x20 (22) Johns Hopkins University Baltimore, MD United States. ROR: https://ror.org/00za53h95 (23) Johns Hopkins Medicine Baltimore, MD United States. ROR: https://ror.org/037zgn354 (24) Johns Hopkins Medicine Baltimore United States. ROR: https://ror.org/037zgn354 (25) Johns Hopkins University Baltimore, Maryland United States. ROR: https://ror.org/00za53h95 (26) Johns Hopkins University Baltimore, MD United States. ROR: https://ror.org/00za53h95 (27) Johns Hopkins University Baltimore, MD United States. ROR: https://ror.org/00za53h95 (28) Johns Hopkins Medicine Baltimore, Maryland United States. ROR: https://ror.org/037zgn354

Tumor-specific antibodies elicited by engineered bacteria promote bladder cancer immunotherapy in preclinical mouse models Spotlight 

Rouanne et al. engineered probiotic E.coli (EcN) using a synchronized lysis integrated circuit to release human CXCL13 at critical population densities, without impeding normal bacterial growth. EcN CXCL13 release promoted B cell and splenocyte migration in vitro and high tumor expression after delivery into mouse bladders. In orthotopic bladder cancer models, EcN-colonized tumors selectively elicited GC responses in tdLNs. EcN boosted anti-PD-1-induced antitumor activity, tumor-specific antibody responses, and long-term survival in “cold” advanced bladder cancer models, and generated immune memory. Efficacy depended on CD8⁺ T and CD4⁺ TFH cells.

Contributed by Paula Hochman

Rouanne et al. engineered probiotic E.coli (EcN) using a synchronized lysis integrated circuit to release human CXCL13 at critical population densities, without impeding normal bacterial growth. EcN CXCL13 release promoted B cell and splenocyte migration in vitro and high tumor expression after delivery into mouse bladders. In orthotopic bladder cancer models, EcN-colonized tumors selectively elicited GC responses in tdLNs. EcN boosted anti-PD-1-induced antitumor activity, tumor-specific antibody responses, and long-term survival in “cold” advanced bladder cancer models, and generated immune memory. Efficacy depended on CD8⁺ T and CD4⁺ TFH cells.

Contributed by Paula Hochman

ABSTRACT: The intratumoral microbiome has recently emerged as a potential hallmark of cancer, with implications for response or resistance to therapy. Bacteria can either promote or inhibit cancer growth. However, intratumoral bacteria can also be engineered using synthetic biology to remodel the tumor microenvironment. Here, we engineered the probiotic bacterium Escherichia coli Nissle 1917 (EcN) to express the human chemokine CXCL13 (C-X-C motif chemokine ligand 13), a critical component of germinal center (GC) formation. Antibody affinity maturation and class switching are fundamental aspects of adaptive immune response. Both occur primarily in the GCs of secondary lymphoid organs for defense against pathogens. Immune checkpoint blockade (ICB) efficacy is primarily driven by T cells; however, recent studies in mice and humans have shown that humoral immune responses act as critical partners for ICB-mediated antitumor activity. Using orthotopic models of bladder cancer, intravesically delivered engineered CXCL13-expressing EcN colonized bladder tumors and elicited GC responses in bladder tumor-draining lymph nodes after intravesical delivery. When combined with programmed cell death protein 1 (PD-1) blockade, engineered EcN improved antitumor activity in two aggressive, fast-growing, and immunologically cold orthotopic mouse models of bladder cancer. Mechanistically, this antitumor effect was dependent on the presence of CD8(+) T cells and CD4(+) T follicular helper cells; combination therapy increased tumor-specific antibody responses and promoted long-term survival and protective immunity upon tumor rechallenge. Thus, we demonstrate that synthetically engineered CXCL13-expressing EcN can enhance the efficacy of PD-1 checkpoint blockade immunotherapy by amplifying tumor-specific humoral immunity.

Author Info: (1) Department of Microbiology & Immunology, Columbia University, New York, NY 10032, USA. Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY 10032, USA.

Author Info: (1) Department of Microbiology & Immunology, Columbia University, New York, NY 10032, USA. Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY 10032, USA. (2) Department of Microbiology & Immunology, Columbia University, New York, NY 10032, USA. Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY 10032, USA. (3) Department of Microbiology & Immunology, Columbia University, New York, NY 10032, USA. Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY 10032, USA. (4) Department of Microbiology & Immunology, Columbia University, New York, NY 10032, USA. (5) Department of Microbiology & Immunology, Columbia University, New York, NY 10032, USA. Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY 10032, USA. (6) Department of Microbiology & Immunology, Columbia University, New York, NY 10032, USA. (7) Department of Microbiology & Immunology, Columbia University, New York, NY 10032, USA. (8) Department of Biomedical Engineering, Columbia University, New York, NY 10027, USA. (9) Department of Urology, Columbia University, New York, NY 10032, USA. (10) Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY 10032, USA. Department of Biomedical Engineering, Columbia University, New York, NY 10027, USA. Data Science Institute, Columbia University, New York, NY 10027, USA. (11) Department of Microbiology & Immunology, Columbia University, New York, NY 10032, USA. Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY 10032, USA.

Modulating the VIP-VIPR pathway reprograms CAR T cells for superior antitumor efficacy in preclinical cancer models Spotlight 

Inspired by clinical data that the neuropeptide vasoactive intestinal peptide (VIP), acting through its receptor (VIPR), was correlated with poor response in patients undergoing CAR therapy, Lin et al. used alpha-fold to design a similarly sized antagonistic peptide (VIPRa) for this immunosuppressive axis, and expressed it with a CAR. During manufacturing, VIPRa-expressing CAR T cells were less activated, but highly activatable, less exhausted, and had a memory phenotype, translating to improved tumor infiltration and in vivo efficacy. CAR/VIPRa T cells were metabolically superior, and more effectively engaged endogenous immunity.

Contributed by Ute Burkhardt

Inspired by clinical data that the neuropeptide vasoactive intestinal peptide (VIP), acting through its receptor (VIPR), was correlated with poor response in patients undergoing CAR therapy, Lin et al. used alpha-fold to design a similarly sized antagonistic peptide (VIPRa) for this immunosuppressive axis, and expressed it with a CAR. During manufacturing, VIPRa-expressing CAR T cells were less activated, but highly activatable, less exhausted, and had a memory phenotype, translating to improved tumor infiltration and in vivo efficacy. CAR/VIPRa T cells were metabolically superior, and more effectively engaged endogenous immunity.

Contributed by Ute Burkhardt

ABSTRACT: Clinical efficacy with chimeric antigen receptor (CAR) T cells is currently limited by numerous factors including poor initial product phenotypes and lack of engagement of endogenous immunity. Vasoactive intestinal peptide (VIP) is an immunosuppressive neuropeptide, and the antagonism of its receptor (VIPR) on T cells potentiates T cell activation. We demonstrated that VIP suppresses CAR T cell function and engineered CAR T cells to secrete a short peptide drug that antagonizes VIPR (CAR/VIPRa). Armored CAR/VIPRa T cells maintained a memory phenotype and were metabolically quiescent after manufacturing yet mounted a strong bioenergetic response after antigen stimulation. Moreover, CAR/VIPRa T cells potentiated endogenous antitumor immunity through the recruitment of host T cells. In syngeneic and xenogeneic mouse models of hematological and solid tumors, CAR/VIPRa T cells exhibited greater tumor infiltration and maintained a less exhausted memory phenotype, resulting in superior antitumor efficacy. Together, these data show that VIPRa peptides produced by armored CAR T cells can enhance T cell function and boost endogenous immunity, thereby improving tumor control.

Author Info: (1) Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA, USA. (2) Department of Hematology and Medical Oncology, Emory University School

Author Info: (1) Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA, USA. (2) Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA, USA. (3) Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA, USA. (4) Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA, USA. (5) George W. Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, GA, USA. (6) Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA, USA. (7) Department of Surgery, Emory University School of Medicine, Atlanta, GA, USA. (8) Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA, USA. (9) Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, GA, USA. (10) Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, GA, USA. (11) Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA, USA. (12) George W. Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, GA, USA. (13) George W. Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, GA, USA. (14) Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA, USA. (15) Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA, USA. (16) Biostatistics Shared Resource, Emory University School of Medicine, Atlanta, GA, USA. (17) Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA, USA. (18) Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA, USA. (19) Cambium Oncology, Atlanta, GA, USA. (20) Achieve Clinics, Los Angeles, CA, USA. (21) Achieve Clinics, Los Angeles, CA, USA. Eldred Advisors, Los Angeles, CA, USA. (22) Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA. (23) Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA. Winship Cancer Institute of Emory University, Atlanta, GA, USA. Aflac Cancer & Blood Disorders Center, Children's Healthcare of Atlanta, Atlanta, GA, USA. (24) Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA, USA. Winship Cancer Institute of Emory University, Atlanta, GA, USA. (25) Department of Surgery, Emory University School of Medicine, Atlanta, GA, USA. Winship Cancer Institute of Emory University, Atlanta, GA, USA. Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA, USA. (26) Department of Surgery, Emory University School of Medicine, Atlanta, GA, USA. Winship Cancer Institute of Emory University, Atlanta, GA, USA. (27) Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, GA, USA. Winship Cancer Institute of Emory University, Atlanta, GA, USA. (28) George W. Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, GA, USA. Winship Cancer Institute of Emory University, Atlanta, GA, USA. Parker H. Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA, USA. Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA, USA. (29) Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA, USA. Winship Cancer Institute of Emory University, Atlanta, GA, USA. (30) Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA, USA. Winship Cancer Institute of Emory University, Atlanta, GA, USA.

Tim-3 Sustains Tumor Treg Stability and Function, Limiting Checkpoint Blockade Therapy Efficacy Spotlight 

Banerjee et al. showed that Tim3 expression on tumor-infiltrating Tregs was required for their survival and suppressive function via Akt-FOXO1 signaling. Treg-specific Tim3 deletion in an MC38 model reduced tumor-infiltrating Tregs and CD25 expression, impaired Treg survival, delayed CD8+ T cell exhaustion, enhanced CD8+ proliferation, and reduced tumor burden, without disrupting peripheral homeostasis. Delayed Tim3 deletion in Tregs was sufficient to slow tumor growth and augment CD8+ responses, and Treg-specific Tim3 loss synergized with ICB in a resistant B16F10 model. In HNSCC, low Tim3 expression correlated with response to anti-PD-1/Lag3 ICB.

Contributed by Shishir Pant

Banerjee et al. showed that Tim3 expression on tumor-infiltrating Tregs was required for their survival and suppressive function via Akt-FOXO1 signaling. Treg-specific Tim3 deletion in an MC38 model reduced tumor-infiltrating Tregs and CD25 expression, impaired Treg survival, delayed CD8+ T cell exhaustion, enhanced CD8+ proliferation, and reduced tumor burden, without disrupting peripheral homeostasis. Delayed Tim3 deletion in Tregs was sufficient to slow tumor growth and augment CD8+ responses, and Treg-specific Tim3 loss synergized with ICB in a resistant B16F10 model. In HNSCC, low Tim3 expression correlated with response to anti-PD-1/Lag3 ICB.

Contributed by Shishir Pant

ABSTRACT: Regulatory T cells (Treg) act as a powerful barrier to effective antitumor immunity. Although manipulating Treg is a promising anticancer strategy, doing so while sparing general immune tolerance has been a challenge. Identifying factors specifically expressed in tumor-infiltrating Treg is therefore important for better understanding cancer pathogenesis and identifying novel therapeutic targets that enhance antitumor immunity. We show that T cell Immunoglobulin and Mucin 3 (Tim-3) expression on tumor Treg is required for the function and survival of these cells, in part through Akt and FOXO1 signaling. Deleting Tim-3 in Treg leads to delayed tumor-specific T-cell exhaustion and lower tumor burden, without altering peripheral homeostasis. Similar effects were noted when Tim-3 was only deleted from half of the Treg or when deletion was delayed until after tumor inoculation. Moreover, Treg-specific deletion of Tim-3 cooperated with PD-1 checkpoint blockade to sensitize an immunotherapy-resistant tumor model. In addition, a decrease in Tim-3+ tumor Treg correlated with responsiveness to PD-1/LAG-3 combination checkpoint blockade in a human clinical trial. Overall, our data provide evidence that Tim3-expressing Treg are a promising target to modulate tumor-specific immune responses.

Author Info: (1) University of Pittsburgh Pittsburgh, PA United States. ROR: https://ror.org/01an3r305 (2) University of Pittsburgh Pittsburgh, PA United States. ROR: https://ror.org/01an3r305

Author Info: (1) University of Pittsburgh Pittsburgh, PA United States. ROR: https://ror.org/01an3r305 (2) University of Pittsburgh Pittsburgh, PA United States. ROR: https://ror.org/01an3r305 (3) University of Pittsburgh Pittsburgh, PA United States. ROR: https://ror.org/01an3r305 (4) University of Pittsburgh Pittsburgh, PA United States. ROR: https://ror.org/01an3r305 (5) University of North Carolina at Chapel Hill Chapel Hill, NC United States. ROR: https://ror.org/0130frc33 (6) University of Pittsburgh Pittsburgh, PA United States. ROR: https://ror.org/01an3r305 (7) University of Pittsburgh Pittsburgh, PA United States. ROR: https://ror.org/01an3r305 (8) University of Pittsburgh Pittsburgh, PA United States. ROR: https://ror.org/01an3r305 (9) University of Pittsburgh Pittsburgh, PA United States. (10) University of North Carolina at Chapel Hill Chapel Hill, NC United States. ROR: https://ror.org/0130frc33 (11) University of Pittsburgh Pittsburgh, PA United States. ROR: https://ror.org/01an3r305 (12) University of North Carolina Hospitals Chapel Hill, NC United States. ROR: https://ror.org/0355zfr67 (13) University of Pittsburgh Pittsburgh, PA United States. ROR: https://ror.org/01an3r305

Mutant KRAS peptide vaccine with dual checkpoint blockade in metastatic colorectal cancer: a phase I trial Spotlight 

Wang et al. evaluated a combination of nivolumab, ipilimumab, and mKRAS-VAX (six 21-mer synthetic long peptides targeting common KRAS mutations) in 13 heavily pretreated patients with MMRp/MSS metastatic colorectal cancer. Treatment was well tolerated, with a 15% overall response rate and a median progression-free and overall survival of 2 and 24.9 months, respectively. Direct ex vivo peptide stimulation revealed reactive T cell responses in 75% of patients, which reached 100% following in vitro expansion (mainly CD4+ and polyfunctional). Tumor infiltration by peripheral mKRAS-reactive T cells was associated with tumor regression.

Contributed by Ute Burkhardt

Wang et al. evaluated a combination of nivolumab, ipilimumab, and mKRAS-VAX (six 21-mer synthetic long peptides targeting common KRAS mutations) in 13 heavily pretreated patients with MMRp/MSS metastatic colorectal cancer. Treatment was well tolerated, with a 15% overall response rate and a median progression-free and overall survival of 2 and 24.9 months, respectively. Direct ex vivo peptide stimulation revealed reactive T cell responses in 75% of patients, which reached 100% following in vitro expansion (mainly CD4+ and polyfunctional). Tumor infiltration by peripheral mKRAS-reactive T cells was associated with tumor regression.

Contributed by Ute Burkhardt

ABSTRACT: Immune checkpoint inhibitors (ICIs) have limited activity in mismatch repair proficient or microsatellite stable (MMRp/MSS) colorectal cancer (CRC). KRAS mutations, present in approximately 40% of these cancers, can generate neoantigens that are targets for therapeutic vaccines. In this single-arm, phase I study (NCT04117087), we evaluated mKRAS-VAX, a pooled mutant KRAS (mKRAS) peptide vaccine targeting six KRAS mutations with nivolumab and ipilimumab in 13 patients with pretreated metastatic MMRp/MSS CRC. Both primary endpoints of safety and immunogenicity (within 17 weeks post-vaccination) were met. Secondary endpoints included treatment efficacy defined by RECIST v1.1 criteria. All adverse events attributed to mKRAS-VAX were grade 1 or 2, and the addition of mKRAS-VAX did not increase the frequency of severe immune-related adverse events beyond the expected profile of dual ICIs alone. mKRAS-VAX elicited an increase in tumor-specific mKRAS-reactive T-cells in 8/12 biomarker-evaluable patients (75%) by direct ex vivo IFN_ ELISpot and in 12 patients (100%) following in vitro expansion. Our findings support further development of mKRAS vaccines with ICIs for advanced MMRp/MSS CRC.

Author Info: (1) Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA. Johns Hopkins Convergence Institute, Johns Hopkins University S

Author Info: (1) Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA. Johns Hopkins Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. The Bloomberg Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University of Medicine, Baltimore, MD, USA. (2) Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA. Johns Hopkins Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. The Bloomberg Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University of Medicine, Baltimore, MD, USA. (3) Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA. Johns Hopkins Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. The Bloomberg Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University of Medicine, Baltimore, MD, USA. Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (4) Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA. (5) Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA. Johns Hopkins Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. The Bloomberg Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University of Medicine, Baltimore, MD, USA. (6) Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA. Johns Hopkins Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. The Bloomberg Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University of Medicine, Baltimore, MD, USA. Department of Hematology/Oncology, Department of Internal Medicine, Vanderbilt University Medical Center, Nashville, TN, USA. (7) Johns Hopkins Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. The Bloomberg Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University of Medicine, Baltimore, MD, USA. Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. (8) Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA. Johns Hopkins Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. The Bloomberg Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University of Medicine, Baltimore, MD, USA. (9) Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA. Johns Hopkins Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. The Bloomberg Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University of Medicine, Baltimore, MD, USA. (10) Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA. (11) Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA. (12) Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA. Johns Hopkins Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. The Bloomberg Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University of Medicine, Baltimore, MD, USA. (13) Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA. Johns Hopkins Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. The Bloomberg Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University of Medicine, Baltimore, MD, USA. (14) Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA. Johns Hopkins Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. The Bloomberg Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University of Medicine, Baltimore, MD, USA. (15) Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA. Johns Hopkins Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. The Bloomberg Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University of Medicine, Baltimore, MD, USA. (16) Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA. Johns Hopkins Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. The Bloomberg Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University of Medicine, Baltimore, MD, USA. (17) Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA. (18) Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA. Johns Hopkins Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. The Bloomberg Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University of Medicine, Baltimore, MD, USA. (19) Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA. Johns Hopkins Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. The Bloomberg Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University of Medicine, Baltimore, MD, USA. (20) Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA. (21) Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA. (22) Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA. Johns Hopkins Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. The Bloomberg Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University of Medicine, Baltimore, MD, USA. (23) Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA. nilo.azad@jhu.edu. Johns Hopkins Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. nilo.azad@jhu.edu. The Bloomberg Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University of Medicine, Baltimore, MD, USA. nilo.azad@jhu.edu. (24) Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA. nzaidi1@jhmi.edu. Johns Hopkins Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. nzaidi1@jhmi.edu. The Bloomberg Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University of Medicine, Baltimore, MD, USA. nzaidi1@jhmi.edu.

A distinct antigen presentation pathway drives potent T cell immunity in lipid nanoparticle-based mRNA vaccines Spotlight 

Muro and Wang et al. studied mechanisms by which lipid nanoparticle-encapsulated mRNA (mRNA-LNP) vaccines induce significantly higher levels of antigen-specific cytotoxic T cells and T cell-dependent antibodies compared to conventional adjuvant-based immunization. Using model antigens, mRNA-LNP induced Th1-skewed murine CD4+ T cell differentiation, followed by production of class-switched IgGs (IgG2b and IgG2c) and long-term cytotoxic CD8+ T cells. Unlike traditional cDC1-mediated cross-presentation, mRNA-LNPs were primarily found in migratory cDC2 cells in draining lymph nodes, resulting in strong, persistent antigen presentation.

Contributed by Katherine Turner

Muro and Wang et al. studied mechanisms by which lipid nanoparticle-encapsulated mRNA (mRNA-LNP) vaccines induce significantly higher levels of antigen-specific cytotoxic T cells and T cell-dependent antibodies compared to conventional adjuvant-based immunization. Using model antigens, mRNA-LNP induced Th1-skewed murine CD4+ T cell differentiation, followed by production of class-switched IgGs (IgG2b and IgG2c) and long-term cytotoxic CD8+ T cells. Unlike traditional cDC1-mediated cross-presentation, mRNA-LNPs were primarily found in migratory cDC2 cells in draining lymph nodes, resulting in strong, persistent antigen presentation.

Contributed by Katherine Turner

ABSTRACT: Lipid nanoparticle-encapsulated mRNA (mRNA-LNP) vaccines trigger the potent differentiation of antigen-specific cytotoxic CD8 T cells in addition to antibody production. Despite its high immunogenicity, the cellular mechanisms by which mRNA-LNP induces such unusual immune responses remain largely unclear. Here, we show that mRNA-LNP induces potent and long-lasting CD8 T cell expansion through an antigen presentation mechanism that differs from that of conventional adjuvants. In mice immunized with mRNA-LNP, the number of antigen-specific CD8 T cells was one order of magnitude higher than that induced by combining antigen proteins with immunostimulants such as lipopolysaccharide or polyinosinic:polycytidinic acid. Intramuscularly administered mRNA-LNPs were mainly taken up by migratory type 2 conventional dendritic cells in draining lymph nodes, resulting in notably strong and persistent antigen presentation through major histocompatibility complex class I. Furthermore, CD8 T cell induction by mRNA-LNP required migratory dendritic cells but not the traditional cross-presentation pathway that is otherwise essential for antiviral and antitumor immunity. Thus, the mRNA-LNP formulation exerts unconventional immune responses through a different antigen-presentation pathway from conventional component vaccines.

Author Info: (1) Department of Immunology, Graduate School of Medicine and Faculty of Medicine, The University of Tokyo, Tokyo, Japan. Division of Molecular Pathology, Research Institute for Bi

Author Info: (1) Department of Immunology, Graduate School of Medicine and Faculty of Medicine, The University of Tokyo, Tokyo, Japan. Division of Molecular Pathology, Research Institute for Biomedical Sciences, Tokyo University of Science, Chiba, Japan. (2) Department of Immunology, Graduate School of Medicine and Faculty of Medicine, The University of Tokyo, Tokyo, Japan. (3) Department of Immunology, Graduate School of Medicine and Faculty of Medicine, The University of Tokyo, Tokyo, Japan. (4) Division of Molecular Pathology, Research Institute for Biomedical Sciences, Tokyo University of Science, Chiba, Japan. (5) Division of Vaccine Science, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan. International Vaccine Design Center, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan. Division of Rheumatology, Department of Medicine, University of California San Diego, La Jolla, CA, United States. (6) Department of Immunology, Graduate School of Medicine and Faculty of Medicine, The University of Tokyo, Tokyo, Japan. (7) Department of Immunology, Graduate School of Medicine and Faculty of Medicine, The University of Tokyo, Tokyo, Japan. Division of Immune Environment Dynamics, Cancer Research Institute, Kanazawa University, Kanazawa, Japan. Immune Network Research Unit, Institute for Frontier Science Initiative InFiniti, Kanazawa University, Kanazawa, Japan. (8) Department of Laboratory Animal Medicine, National Institute of Global Health and Medicine, Japan Institute for Health and Security (JIHS), Tokyo, Japan. (9) Department of Laboratory Animal Medicine, National Institute of Global Health and Medicine, Japan Institute for Health and Security (JIHS), Tokyo, Japan. (10) Kyoto University Immunomonitoring Center, Liaison Office, Kyoto University, Kyoto, Japan. Department of Immunology, Graduate School of Medicine, Kyoto University, Kyoto, Japan. (11) Division of Vaccine Science, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan. International Vaccine Design Center, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan. (12) Department of Immunology, Graduate School of Medicine and Faculty of Medicine, The University of Tokyo, Tokyo, Japan. Division of Molecular Pathology, Research Institute for Biomedical Sciences, Tokyo University of Science, Chiba, Japan. (13) Department of Immunology, Graduate School of Medicine and Faculty of Medicine, The University of Tokyo, Tokyo, Japan.

IL7-Receptor-Targeted CAR T-Cell Therapy for T-Cell Acute Lymphoblastic Leukemia Spotlight 

Hocine, Ganbaatar, and Amador-Molina et al. developed an IL7Rα (CD127)-targeted chimeric antigen receptor (CAR) T cells and demonstrated their efficacy against T-ALL in vitro and in vivo, including in a patient-derived xenograft model using matched patient-derived CAR T cells. Low-affinity CAR T cells outperformed high-affinity cells, but maintained higher expression of CD127, putting them at risk of fratricide after tumor eradication. To reduce fratricide, genetic KO of CD127, a natural selection method, and co-culture with dasatinib (a tyrosine kinase inhibitor), during manufacturing were each tested, with dasatinib emerging as the most viable option.

Contributed by Lauren Hitchings

Hocine, Ganbaatar, and Amador-Molina et al. developed an IL7Rα (CD127)-targeted chimeric antigen receptor (CAR) T cells and demonstrated their efficacy against T-ALL in vitro and in vivo, including in a patient-derived xenograft model using matched patient-derived CAR T cells. Low-affinity CAR T cells outperformed high-affinity cells, but maintained higher expression of CD127, putting them at risk of fratricide after tumor eradication. To reduce fratricide, genetic KO of CD127, a natural selection method, and co-culture with dasatinib (a tyrosine kinase inhibitor), during manufacturing were each tested, with dasatinib emerging as the most viable option.

Contributed by Lauren Hitchings

ABSTRACT: On the basis that T-cell acute lymphoblastic leukemia (T-ALL) cells overexpress IL7 receptor (IL7R), which promotes resistance to chemotherapy and disease relapse, here we develop IL7Rα (CD127)-targeted chimeric antigen receptor (CAR) T cells with low- and high-affinity single-chain variable fragments. We establish the antitumor efficacy of CD127 CAR against T-ALL cells in vitro, in female mouse models of T-ALL, and against blasts from patients with T-ALL using the patients' own T cells transduced with CD127 CAR. Antitumor efficacy is higher with low-affinity CAR T cells than high-affinity CAR T cells, albeit with fratricide of CAR T cells following eradication of CD127-overexpressing blasts. CRISPR-Cas9 knockout of CD127 eliminates fratricide at the risk of prolonged lymphopenia in vivo. To overcome fratricide, we investigate short-term ( < 7 days) co-culture with or without dasatinib, a tyrosine kinase inhibitor, versus a natural selection method (10 days) and demonstrate that co-culturing with dasatinib facilitates higher CAR T-cell yield, improved fitness, and preserved functionality. In vivo, dasatinib can be used to temporarily and reversibly suppress CAR T-cell activity. With this supporting translational data, we are initiating a trial with low-affinity CD127 CAR T cells for adult and pediatric patients with relapsed or refractory T-ALL.

Author Info: (1) Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (2) Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer

Author Info: (1) Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (2) Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (3) Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (4) Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (5) Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (6) Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (7) Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (8) Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York, USA. (9) Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (10) Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (11) Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (12) Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (13) Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York, USA. (14) Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York, USA. (15) Cellular Therapy Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, USA. (16) Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York, USA. (17) Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA. adusumip@mskcc.org. Cellular Therapy Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, USA. adusumip@mskcc.org.

Generalizable AI predicts immunotherapy outcomes across cancers and treatments Spotlight 

Shen et al. developed COMPASS, an AI model that interprets pre-treatment tumor RNAseq data in the context of tumor-immune gene expression modules and maps them to predict ICB response. Trained on TCGA and cohort data, COMPASS was applicable across cohorts, indications, ICB drugs, and targets, with superior response prediction compared to established models or correlates (TMB, PD-L1). COMPASS also generated personalized “response maps” identifying potential resistance mechanisms; unexpected nonresponders (i.e. patients with an inflammatory TME) often had gene expression associated with angiogenesis, TGFβ, and B cell deficiency.

Contributed by Alex Najibi

Shen et al. developed COMPASS, an AI model that interprets pre-treatment tumor RNAseq data in the context of tumor-immune gene expression modules and maps them to predict ICB response. Trained on TCGA and cohort data, COMPASS was applicable across cohorts, indications, ICB drugs, and targets, with superior response prediction compared to established models or correlates (TMB, PD-L1). COMPASS also generated personalized “response maps” identifying potential resistance mechanisms; unexpected nonresponders (i.e. patients with an inflammatory TME) often had gene expression associated with angiogenesis, TGFβ, and B cell deficiency.

Contributed by Alex Najibi

ABSTRACT: Immune checkpoint inhibitors (ICIs) are a standard treatment across cancers, yet most patients do not respond, and existing biomarkers generalize poorly across tumor types and therapies. Here we present COMPASS, a pan-cancer foundation model that predicts immunotherapy response from bulk tumor transcriptomes using a concept bottleneck transformer. COMPASS encodes gene expression through 44 biologically grounded immune concepts representing immune cell states, tumor-microenvironment interaction and signaling pathways. Trained on 10,184 tumors across 33 cancer types, COMPASS achieves better average performance than 22 methods across 16 clinical cohorts spanning seven cancers and six ICIs, improving accuracy by 8.5% and area under the precision-recall curve by 15.7% on average across cohorts. COMPASS generalizes to cancer types and treatments not represented during fine-tuning and may inform indication selection and patient stratification. In survival analyses, patients classified by COMPASS as responders had longer overall survival (hazard ratio_=_4.7, P_<_0.0001). Personalized response maps connect gene expression to immune concepts, identifying programs associated with response and resistance; in immune-inflamed non-responders, COMPASS highlights programs including TGF_ signaling, endothelial exclusion, CD4(+) T cell dysfunction and B cell deficiency. COMPASS predicts immunotherapy response and provides hypothesis-generating mechanistic insight for trial design and translational studies.

Author Info: (1) Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA. College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China. (2) Department of Biome

Author Info: (1) Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA. College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China. (2) Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA. (3) Division of Immunology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA. (4) Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA. (5) Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA. (6) Roche Pharma Research and Early Development, Oncology Early Clinical Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Basel, Switzerland. (7) Computational Sciences Center of Excellence, F. Hoffmann-La Roche Ltd., Basel, Switzerland. daniel.marbach.dm1@roche.com. (8) Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA. marinka@hms.harvard.edu. Kempner Institute for the Study of Natural and Artificial Intelligence, Harvard University, Allston, MA, USA. marinka@hms.harvard.edu. Broad Institute of MIT and Harvard, Cambridge, MA, USA. marinka@hms.harvard.edu. Harvard Data Science Initiative, Cambridge, MA, USA. marinka@hms.harvard.edu.

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