KRAS peptide vaccine / Sidney Kimmel Comprehensive Cancer Center - LARVOL DELTA

IRB00210915: Pooled Mutant KRAS-Targeted Long Peptide Vaccine Combined With Nivolumab and Ipilimumab for Patients With Resected Mismatch Repair Protein (MMR-p) Colorectal and Pancreatic Cancer (clinicaltrials.gov) - P1 | N=27 | Active, not recruiting | Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | Trial completion date: Aug 2025 ➔ Jun 2027 | Trial primary completion date: Aug 2025 ➔ Jun 2027

Mismatch repair • Trial completion date • Trial primary completion date • Colorectal Cancer • Oncology • Pancreatic Cancer • Solid Tumor • KRAS

A mutant KRAS peptide vaccine (mKRAS-VAX) combined with immune checkpoint blockade recruits vaccine-induced T-cells into metastatic MMRp/MSS colorectal tumors (SITC 2025) - P1 | "We conducted a Phase 1 (NCT04117087) study of mKRAS-VAX with nivolumab and ipilimumab in patients with MMRp/MSS mCRC refractory to fluoropyrimidines, irinotecan, and oxaliplatin...A Phase 1b trial (NCT06411691) combining mKRAS-VAX with ICIs balstilimab and botensilimab in advanced MMRp/MSS CRC and pancreatic ductal adenocarcinoma is underway.Trial Registration The study was registered at ClinicalTrials.gov (NCT04117087).Ethics Approval The study protocol and all amendments were approved by the institutional review board at Johns Hopkins University (IRB00210915). The study was conducted in accordance with the Declaration of Helsinki and good clinical practice guidelines. All participants provided written informed consent."

Checkpoint block • Checkpoint inhibition • IO biomarker • Metastases • Colorectal Cancer • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • IFNG • KRAS • TRB

KRAS Peptide Vaccine Combined With Chemotherapy, Nivolumab and Ipilimumab in Advanced KRAS Mutated Non-Small Cell Lung Cancer (IASLC-WCLC 2025) - "The vaccine consists of poly-ICLC adjuvant admixed with pooled synthetic long peptides (SLPs) corresponding to six common mKRAS subtypes: G12D, G12R, G12V, G12A, G12C, and G13D. Correlative studies will apply multi-omic approaches to identify markers of response and resistance in tumor and plasma samples. The study has enrolled 5 patients to treatment with the combination of ipilimumab and nivolumab with KRAS-mutant vaccine and we will now procced to enroll additional patients to the amendment described herein."

IO biomarker • Metastases • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KEAP1 • KRAS • STK11

IRB00210915: Pooled Mutant KRAS-Targeted Long Peptide Vaccine Combined With Nivolumab and Ipilimumab for Patients With Resected Mismatch Repair Protein (MMR-p) Colorectal and Pancreatic Cancer (clinicaltrials.gov) - P1 | N=27 | Active, not recruiting | Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | Recruiting ➔ Active, not recruiting

Enrollment closed • Colorectal Cancer • Oncology • Pancreatic Cancer • Solid Tumor • KRAS

Peptide inhibitors: Breaking cancer code. (PubMed, Eur J Med Chem) - "Key examples include RAS-targeting peptides such as KRpep-2D, cyclo-CRVLIR, L5UR, RAS-binding peptide (RBP), the mutant KRAS peptide vaccine combined with Nivolumab and Ipilimumab, cyclorasin B4-27, and LUNA18, as well as mTOR-targeting peptides like P1_WT, PDHK1-241aa, TRIM1-269aa, and the micropeptide human small regulatory polypeptide of amino acid response (hSPAR). Among these, the mutant KRAS peptide vaccine (with Nivolumab and Ipilimumab) and LUNA18 demonstrate promising clinical potential and are currently undergoing trials."

Journal • Review • Oncology • Sarcoma • Solid Tumor • KRAS • MID2

Comparing Neoadjuvant/Adjuvant GVAX vs a mKRASvax Given With Anti-PD-1 and Anti-CD137 for Surgically Resectable Pancreatic Cancer (clinicaltrials.gov) - P1/2 | N=38 | Recruiting | Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | Not yet recruiting ➔ Recruiting

Enrollment open • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • Solid Tumor • KRAS

Mutant KRAS peptide vaccine combined with ipilimumab/nivolumab in advanced mismatch repair proficient/microsatellite stable (MMRp/MSS) colorectal cancer: Preliminary analysis from a phase I study (AACR 2025) - P1 | "Key inclusion criteria included tumor expression of a KRAS mutation included in mKRAS-VAX and prior 5-fluorouracil, oxaliplatin, and irinotecan exposure. mKRAS-VAX and ipi/nivo is well-tolerated and induced mKRAS-specific T-cell responses. Moreover, this strategy resulted in meaningful clinical responses in chemorefractory metastatic mKRAS MMRp/MSS CRC with OS that was provocative. Ongoing studies of the T cell repertoire in blood and tumor tissue will be used to identify biomarkers that predict response to mKRAS-targeted immunotherapy."

IO biomarker • Metastases • Mismatch repair • P1 data • pMMR • Colorectal Cancer • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • IFNG • KRAS

Antigen-presenting CAFs in PDAC differentially regulate Treg phenotype and function via CXCL9 and CCL22 (AACR 2025) - "All mouse strains were untreated, treated with ICB or anti-mesothelin antibody, or immunized with a KRAS peptide vaccine... apCAFs are more abundant in immunosensitive PDAC tumors, spatially involved with CD4+ T cells, and are functionally relevant for response to ICB as shown by two depletion models. Notably, chemokine signaling from apCAFs varies with tumor of origin and modulates Treg function. Together these data implicate apCAFs as important mediators of the antitumor immune response."

Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • CAFs • CCL2 • CCL22 • CD4 • CXCL9 • KRAS • PDGFRA

Comparing Neoadjuvant/Adjuvant GVAX vs a mKRASvax Given With Anti-PD-1 and Anti-CD137 for Surgically Resectable Pancreatic Cancer (clinicaltrials.gov) - P1/2 | N=38 | Not yet recruiting | Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

IO biomarker • New P1/2 trial • Hepatology • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • Solid Tumor • CD20

Antigen-presenting CAFs are required for immunotherapy-mediated tumor response in PDAC tumors (SITC 2024) - "Mice were untreated, treated with dual checkpoint inhibition, or immunized with a KRAS peptide vaccine...Although a small proportion of the TME, apCAFs may be enhanced in number and function by CAF-targeted modulators to affect the antitumor response. Such a strategy could provide a solution to the currently unmet need of new and more effective treatments for PDAC patients."

IO biomarker • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • CAFs • CD4 • ITGAX • KRAS • PDGFRA

Antigen-presenting cancer-associated fibroblasts are required for ICI-sensitivity in pancreatic ductal adenocarcinoma (AACRPanCa 2024) - "Mice were untreated, treated with dual checkpoint inhibition, or immunized with a KRAS peptide vaccine... apCAFs are more abundant and more proximal to CD4 T cells in immunosensitive tumors, and apCAF KO sKPC tumor-bearing mice lose sensitivity to ICI. Together these data implicate apCAFs as essential mediators of the antitumor immune response. The unique transcriptome of apCAFs and cocultured CD4 T cells depending on tumor of origin suggests multiple strategies to modulate their interactions."

Fibrosis • Gastrointestinal Cancer • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • CAFs • CD4 • ITGAX • KRAS • PDGFRA

Harnessing the immune system against mutant KRAS (CRI-ENCI-AACR ICIC 2024) - "In our initial phase I study, we tested the safety and immunogenicity of a pooled synthetic long peptide vaccine targeting the six most common KRAS mutations in combination with anti-PD-1 (nivolumab) and anti-CTLA-4 (ipilimumab) antibodies in patients with resected PDAC (NCT5013216)...Together, these initial studies demonstrate the safety and favorable immunogenicity profile of our mutated KRAS peptide vaccine, while also defining a novel library of mKRAS-reactive TCRs targeting the six most common KRAS mutations found in PDAC...Our preliminary analysis demonstrates a similar safety and activation of mKRAS specific T cells in the peripheral blood in a cohort of high-risk individuals with inherited predisposition of PDAC. These findings serve as proof-of-concept to advance vaccine strategies focused on intercepting the development of PDAC in high-risk populations."

IO biomarker • Gastrointestinal Cancer • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • CD4 • CD8 • KRAS

An off-the-shelf vaccine activates mutant KRAS-specific T cells in patients with resected pancreatic cancer (AACR 2024) - P1 | "In a phase I study, we evaluated mKRAS-specific T cell responses raised by the vaccine when given in combination with immune checkpoint inhibitors to PDAC patients following resection and adjuvant chemotherapy.Materials and Patients received the pooled mKRAS peptide vaccine (0.3mg/peptide and 0.5mg poly-ICLC weekly for 4 doses in combination with ipilimumab and nivolumab followed by boosters every 8 weeks with nivolumab. This study demonstrates mKRAS vaccine induction of de novo, high quality mKRAS-specific polyfunctional CD4+ and CD8+ T cells. mKRAS-specific TCR analysis identified shared public TCRs across vaccinated patients that have important implications for future "off the shelf" adoptive therapy approaches. Ongoing studies are aimed to validate antigen specificity and map HLA-restriction of mKRAS-specific T cells."

Clinical • IO biomarker • Gastrointestinal Cancer • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • CCR7 • CD4 • CD8 • GZMB • IFNG • IL2 • KRAS • TNFRSF9

Pooled Mutant KRAS-Targeted Long Peptide Vaccine Combined With Nivolumab and Ipilimumab for Patients With Resected Mismatch Repair Protein (MMR-p) Colorectal and Pancreatic Cancer (clinicaltrials.gov) - P1 | N=30 | Recruiting | Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | Trial completion date: Dec 2024 ➔ Aug 2025 | Trial primary completion date: Dec 2024 ➔ Aug 2025

Mismatch repair • Trial completion date • Trial primary completion date • Colorectal Cancer • Gastrointestinal Cancer • Hepatology • Oncology • Pancreatic Cancer • Solid Tumor • CD4 • CD8 • KRAS

Barcoding intracellular reverse transcription enables high-throughput phenotype-coupled T cell receptor analyses. (PubMed, Cell Rep Methods) - "We used INCERTS to discover antigen-specific TCRs from patients with cancer immunized with a novel mutant KRAS peptide vaccine. After ex vivo stimulation, 28 uniquely barcoded samples were pooled prior to FACS into peptide-reactive and non-reactive CD4 and CD8 populations. Combining complementary patient-matched single-cell RNA sequencing (scRNA-seq) data enabled retrieval of full-length, paired TCR alpha and beta chain sequences for future validation of therapeutic utility."

IO biomarker • Journal • Oncology • CD4 • CD8 • KRAS

A pooled mutant KRAS peptide vaccine activates polyfunctional T cell responses in patients with resected pancreatic cancer (AACR 2023) - P1 | "Patients with no evidence of disease on imaging within 6 months of completion of adjuvant chemotherapy were vaccinated with the mKRAS vaccine (0.3mg/peptide and 0.5mg poly-ICLC (Hiltonol: Oncovir)) weekly for 4 doses followed by booster vaccines every 8 weeks. Patients also received ipilimumab (1mg/kg, every 6 weeks for 2 doses) and nivolumab (3mg/kg, every 3 weeks in the priming phase) followed by nivolumab (480mg, flat dose in boost phase)... This study thus far indicates the induction of de novo, high quality mKRAS-specific T cells in the periphery post-vaccine. Ongoing studies will define TCR diversity and clonality of mKRAS-specific T cells to each mKRAS epitope. Overall, our data will be used to identify peripheral T cell-based biomarkers that may be able to predict response to mKRAS-targeted immunotherapy."

Clinical • IO biomarker • Late-breaking abstract • Gastrointestinal Cancer • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • CD4 • CD8 • HLA-DRB1 • IFNG • IL2 • KRAS • TNFA

Pooled Mutant KRAS-Targeted Long Peptide Vaccine Combined With Nivolumab and Ipilimumab for Patients With Resected MMR-p Colorectal and Pancreatic Cancer (clinicaltrials.gov) - P1 | N=30 | Recruiting | Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | Trial completion date: Jun 2024 ➔ Dec 2024 | Trial primary completion date: Jun 2024 ➔ Dec 2024

Trial completion date • Trial primary completion date • Colorectal Cancer • Gastrointestinal Cancer • Hepatology • Oncology • Pancreatic Cancer • Solid Tumor • CD4 • CD8 • KRAS

Pooled Mutant KRAS-Targeted Peptide Vaccine with Nivolumab and Ipilimumab in Advanced KRAS Mutated Non-Small Cell Lung Cancer (IASLC-WCLC 2022) - "Through preclinical and early (ongoing) clinical trial data, our institution has shown the benefits of combining targeted synthetic long peptide vaccines with ICB and adjuvant stimulants in treatment of solid malignancies. This is a single institution, phase I study for patients with Stage III/IV unresectable KRAS-mutated NSCLC to evaluate safety of the pooled mutant-KRAS peptide vaccine with poly-ICLC adjuvant in combination with nivolumab and ipilimumab in the first line treatment setting. The secondary objectives are to assess the impact of therapy on mutant-KRAS specific T cell responses in the peripheral blood and estimate the progression free survival (PFS) for patients treated with this combination. Correlative studies will assess the impact of predicted KRAS mutations on mutant-KRAS specific T cell responses in the peripheral blood, as well as evaluate dynamic genomic alterations of response and resistance through ctDNA analysis."

IO biomarker • Immune Modulation • Immunology • Inflammation • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • ALK • EGFR • KEAP1 • KRAS • STK11

Mutant KRAS -Targeted Long Peptide Vaccine for Patients at High Risk of Developing Pancreatic Cancer (clinicaltrials.gov) - P1 | N=25 | Recruiting | Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | Not yet recruiting ➔ Recruiting

Enrollment open • Colorectal Cancer • Gastrointestinal Cancer • Hepatology • Oncology • Pancreatic Cancer • Solid Tumor • ATM • BRCA1 • BRCA2 • CD4 • CD8 • CDKN2A • EPCAM • IFNG • KRAS • MLH1 • MSH2 • MSH6 • PMS1

Mutant Kirsten Rat Sarcoma (KRAS) -Targeted Long Peptide Vaccine for Patients at High Risk of Developing Pancreatic Cancer (clinicaltrials.gov) - P1; N=25; Not yet recruiting; Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins; Trial completion date: Dec 2025 ➔ Mar 2026; Initiation date: Dec 2021 ➔ Mar 2022; Trial primary completion date: Dec 2025 ➔ Mar 2026

Clinical • Preclinical • Trial completion date • Trial initiation date • Trial primary completion date • Colorectal Cancer • Gastrointestinal Cancer • Hepatology • Oncology • Pancreatic Cancer • Sarcoma • Solid Tumor • BRCA1 • BRCA2 • CD4 • CD8 • CDKN2A • EPCAM • IFNG • KRAS • MLH1 • MSH2 • MSH6 • PMS1

Mutant Kirsten Rat Sarcoma (KRAS) -Targeted Long Peptide Vaccine for Patients at High Risk of Developing Pancreatic Cancer (clinicaltrials.gov) - P1; N=25; Not yet recruiting; Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Clinical • New P1 trial • Preclinical • Colorectal Cancer • Gastrointestinal Cancer • Hepatology • Oncology • Pancreatic Cancer • Sarcoma • Solid Tumor • BRCA1 • BRCA2 • CD4 • CD8 • CDKN2A • EPCAM • IFNG • KRAS • MLH1 • MSH2 • MSH6 • PMS1

Inhibition of lung tumorigenesis by a small molecule CA170 targeting the immune checkpoint protein VISTA. (PubMed, Commun Biol) - "Remarkably, lung tumor development was almost completely suppressed when CA170 was combined with an MHCII-directed KRAS peptide vaccine. Flow cytometry and single-cell RNA sequencing (scRNA-seq) revealed that CA170 increased CD8 T cell infiltration and enhanced their effector functions by decreasing the tumor infiltration of myeloid-derived suppressor cells (MDSCs) and Regulatory T (Treg) cells, while the Kras vaccine primarily induced expansion of CD4 effector T cells. VISTA antagonism by CA170 revealed strong efficacy against lung tumorigenesis with broad immunoregulatory functions that influence effector, memory and regulatory T cells, and drives an adaptive T cell tumor-specific immune response that enhances the efficacy of the KRAS vaccine."

Journal • Immune Modulation • Inflammation • Lung Cancer • Oncology • Solid Tumor • CD4 • CD8 • KRAS

[VIRTUAL] Inhibition of lung tumorigenesis by a novel small molecule CA170 targeting the immune checkpoint protein VISTA (AACR 2021) - "Remarkably, lung tumor development was almost completely suppressed when CA170 was combined with an MHC-II-directed KRAS peptide vaccine. Flow cytometry and single cell RNA sequencing (scRNA-seq) revealed that CA170 increases CD8+ T cell infiltration and effector functions by decreasing the tumor infiltration of myeloid derived suppressor cells (MDSCs) and regulatory T cells (Tregs), while the KRAS vaccine primarily induces expansion of CD4+ effector T cells. Inhibition of VISTA by CA170 has strong efficacy against lung tumorigenesis with broad immunoregulatory functions that influence effector, memory and regulatory T cells, and promotes an adaptive T cell tumor-specific immune response that enhances efficacy of the KRAS vaccine."

Lung Cancer • Oncology • Solid Tumor • CD4 • CD8 • KRAS • PD-L1 • PD-L2

Pooled Mutant KRAS-Targeted Long Peptide Vaccine Combined With Nivolumab and Ipilimumab for Patients With Resected MMR-p Colorectal and Pancreatic Cancer (clinicaltrials.gov) - P1; N=30; Recruiting; Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins; Not yet recruiting ➔ Recruiting

Clinical • Enrollment open • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Pancreatic Cancer • Solid Tumor • CD8 • KRAS

Potentiation of Kras peptide cancer vaccine by avasimibe, a cholesterol modulator. (PubMed, EBioMedicine) - "Avasimibe complements the efficacy of a multi-peptide Kras vaccine in controlling lung cancer development and growth. This treatment regimen represents a novel immunoprevention approach to prevent lung cancer."

Journal