KRAS Vaccine Combo for Colorectal and Pancreatic Cancer

Overseen By Joann Santmyer, RN

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Must not be taking: Immunotherapy, Corticosteroids

Disqualifiers: Brain metastases, Autoimmune disease, HIV, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: Unknown

Duration: 3 years

54 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new combination of treatments for advanced colorectal and pancreatic cancers that cannot be surgically removed. The study examines how a KRAS vaccine, along with two other medicines, impacts the immune system and overall effectiveness against these cancers. Individuals with colorectal or pancreatic cancer who have a specific KRAS mutation and have already undergone some chemotherapy might be suitable candidates. The goal is to determine if this combination can outperform current treatments. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new therapy.

Do I need to stop my current medications to join the trial?

The trial protocol does not specify if you need to stop taking your current medications. However, you cannot be on active immunosuppressive agents or chronic systemic corticosteroids within 14 days of the vaccine treatment.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research shows that the KRAS vaccine is safe for patients with pancreatic cancer. No serious side effects were reported, though some people experienced mild skin redness. This suggests the vaccine is likely well-tolerated in humans.

For Botensilimab, studies indicate it has a manageable safety profile, with expected and non-severe side effects. Importantly, no new immune-related issues emerged, which is a positive sign for safety.

Balstilimab, often used with Botensilimab, also has a manageable safety profile according to studies. This combination did not cause any new significant immune-related problems, which is encouraging.

Since this trial is in its early phase, the main goal is to assess the safety of these treatments. Safety data collection is ongoing. However, previous research provides a hopeful outlook on their tolerability. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Unlike standard treatments for colorectal and pancreatic cancer, which often include chemotherapy and targeted therapies, this new approach combines a KRAS vaccine with two immune checkpoint inhibitors, Balstilimab and Botensilimab. The vaccine specifically targets KRAS mutations, which are common in these cancers, potentially offering a more precise attack against cancer cells. Additionally, the use of Poly-ICLC as an adjuvant aims to boost the immune response even further. Researchers are excited because this combination could enhance the body’s immune system to recognize and destroy cancer cells more effectively than existing treatments.

What evidence suggests that this trial's treatments could be effective for colorectal and pancreatic cancer?

Research has shown that the synthetic long peptide mutant KRAS vaccine (SPL mKRASvax) could play a crucial role in targeting specific cancer mutations. It trains the immune system to attack cancer cells with KRAS mutations, commonly found in pancreatic and colorectal cancers. Patients who received this vaccine demonstrated promising immune responses.

In this trial, participants will receive a combination of SPL mKRASvax, Botensilimab, and Balstilimab. Studies indicate that Botensilimab and Balstilimab together can lead to an average survival time of about 21 months for patients with certain types of colorectal cancer. This combination has achieved a 42% survival rate over two years, considered a strong outcome for this type of cancer. Together, these treatments aim to enhance the body's ability to fight cancer more effectively. ^{2 3 6 7 8}

Who Is on the Research Team?

Nilofer Azad, MD

Principal Investigator

SKCCC Johns Hopkins Medical Institution

Are You a Good Fit for This Trial?

This trial is for patients with stage IV MMR-p colorectal or pancreatic ductal cancer who have measurable disease after first-line FOLFIRINOX/FOLFOXIRI treatment. Specific eligibility criteria are not provided, but typically include factors like age, health status, and previous treatments.

Inclusion Criteria

I am using an approved method of birth control.

Ability to understand and sign a written informed consent document

My cancer tissue is available for advanced genetic testing.

Exclusion Criteria

I am eligible for surgery to remove my cancer.

I have not needed treatment for an autoimmune disease in the last 5 years.

I have fluid buildup in my chest or abdomen.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive the synthetic long peptide mutant KRAS vaccine (SPL mKRASvax) combined with Balstilimab and Botensilimab

3 years

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 months

Extension

Participants may continue to be monitored for progression-free survival and other outcomes

3 years

What Are the Treatments Tested in This Trial?

Interventions

• Balstilimab
• Botensilimab
• KRAS Vaccine with Poly-ICLC adjuvant

Trial Overview The study is testing a new KRAS vaccine combined with two immunotherapy drugs: Balstilimab and Botensilimab. It's in phase 1 to see how effective this combo is against certain types of advanced colorectal and pancreatic cancers.

How Is the Trial Designed?

Group I: SLP mKRASvax (Up to 1.8mg peptide + 0.5 mg Poly-ICLC (Hiltonol), Botensilimab and Balstilimab Experimental Treatment 3 Interventions

Who Is Running the Clinical Trial?

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Lead Sponsor

Trials

578

Recruited

33,600+

Agenus Inc.

Industry Sponsor

Trials

58

Recruited

4,900+

Private Philanthropic Funds

Collaborator

Trials

4

Recruited

150+

National Institutes of Health (NIH)

Collaborator

Trials

2,896

Recruited

8,053,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

United States Department of Defense

Collaborator

Trials

940

Recruited

339,000+

Private Philanthropic Funds

Collaborator

Published Research Related to This Trial

Coculturing cytokine-induced killer cells (CIKs) with K-ras dendritic cells (K-ras-DCs) significantly enhances the proliferation and cancer-killing ability of CIKs against pancreatic cancer cell lines, particularly PANC-1.

K-ras-DCCIKs demonstrated a higher tumor suppression rate compared to standard cytotoxic T lymphocytes (CTLs), indicating their potential as an effective immunotherapy for pancreatic cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The therapeutic effect of cytokine-induced killer cells on pancreatic cancer enhanced by dendritic cells pulsed with K-ras mutant peptide. Tan, G., Zhang, X., Feng, H., et al.[2021]

In a study of 105 patients with advanced pan-cancer treated with immune checkpoint inhibitors (ICIs), specific blood parameters such as lower relative lymphocyte count and higher absolute eosinophil count were identified as predictors for the occurrence of immune-related adverse events (irAEs).

Patients experiencing any grade of irAE had significantly better progression-free survival (PFS) and overall survival (OS), suggesting a potential correlation between the occurrence of irAEs and improved clinical outcomes in ICI therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Analysis of characteristics and predictive factors of immune checkpoint inhibitor-related adverse events. Bai, R., Chen, N., Chen, X., et al.[2021]

Influenza vaccination (FV) in patients with advanced thoracic cancer receiving immune checkpoint inhibitors (ICIs) is associated with a reduced severity of immune-related adverse events (IRAEs), suggesting it may be a safe option for these patients.

The study found that FV significantly decreases the risk of severe IRAEs (grade 3-5) without affecting overall survival rates, indicating that vaccination does not increase treatment toxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Associations of influenza vaccination with severity of immune-related adverse events in patients with advanced thoracic cancers on immune checkpoint inhibitors. Lin, EP., Huang, LC., Whisenant, J., et al.[2023]

In a systematic review of 59 randomized controlled trials involving 41,757 patients, immune checkpoint inhibitors (ICIs) were found to be associated with a 0.93% incidence of all-grade pancreatitis and higher rates of pancreatic enzyme elevations, indicating a notable risk of pancreatic adverse events (AEs) during treatment.

The study revealed that PD-1 inhibitors carry a greater risk of pancreatic AEs compared to PD-L1 inhibitors, and patients receiving dual ICI therapy face an even higher risk than those on single ICI therapy, highlighting the need for clinician awareness regarding these potential complications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pancreatic adverse events of immune checkpoint inhibitors therapy for solid cancer patients: a systematic review and meta-analysis. Zhao, Z., Zhang, W., Pang, L., et al.[2023]

KRAS mutation-based cancer vaccines have shown promise in inducing strong immune responses against tumors in patients with KRAS-driven cancers, as highlighted by encouraging results from both preclinical and clinical studies.

Despite their potential, the effectiveness of these vaccines may be limited by the tumor microenvironment's immunosuppressive factors, suggesting that combining these vaccines with other therapies could enhance their efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cancer vaccines: Targeting KRAS-driven cancers. Zhang, Y., Ma, JA., Zhang, HX., et al.[2021]

The dendritic cell (DC) vaccine modified with tumor lysate and Interleukin-18 (IL-18) significantly enhanced immune responses in a mouse model of pancreatic carcinoma, leading to higher levels of IL-18 and IFN-gamma compared to other treatment groups.

Mice treated with the DC-IL18-Lysate vaccine remained tumor-free for at least 50 days and had a median survival of over 62 days, which was significantly longer than other groups, indicating its potential efficacy as a therapeutic vaccine against pancreatic cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The immunotherapeutic effect of dendritic cells vaccine modified with interleukin-18 gene and tumor cell lysate on mice with pancreatic carcinoma. Tang, ZH., Qiu, WH., Wu, GS., et al.[2019]

Current immune checkpoint inhibitors approved by the US FDA show limited effectiveness in treating gastrointestinal cancers like colorectal and pancreatic cancer.

Combining these checkpoint inhibitors with experimental cancer vaccines may enhance their efficacy, potentially offering new treatment strategies for these challenging cancers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Vaccines and immune checkpoint inhibitors: a promising combination strategy in gastrointestinal cancers. Bashir, B., Flickinger, JC., Snook, AE.[2022]

In a study of 201 older lung cancer patients treated with immune checkpoint inhibitors, the most common immune-related adverse events (irAEs) were interstitial pneumonia (17.2%), dermatological toxicity (16.1%), and hypothyroidism (5.6%).

The Geriatric-8 (G-8) assessment tool was effective in predicting the occurrence of irAEs in patients aged 65-71 years, with high accuracy (AUC of 0.757 for ≥G2 irAEs and 0.862 for ≥G3 irAEs), while other factors like lower CD4+ T cells and certain comorbidities were also linked to increased risk of irAEs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Predictors of immune checkpoint inhibitor-related adverse events in older patients with lung cancer: a prospective real-world analysis. Gao, J., Zhang, P., Tang, M., et al.[2023]

The K-ras peptide vaccine for patients with resected pancreatic cancer was found to be safe, with no severe toxicities reported, although mild erythema at the injection site was common (94%).

Out of 24 vaccinated patients, only 11% showed a specific immune response to the K-ras mutation, and while median overall survival was 20.3 months, the vaccine's efficacy remains unproven, suggesting a need for more immunogenic vaccine strategies in future studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Targeting mutated K-ras in pancreatic adenocarcinoma using an adjuvant vaccine. Abou-Alfa, GK., Chapman, PB., Feilchenfeldt, J., et al.[2020]

A comprehensive review of 41 randomized controlled trials involving 23,121 patients found that treatments combining chemotherapy with immune checkpoint inhibitors (ICIs) significantly increased the risk of treatment-related adverse events compared to ICI-only regimens.

Among the various ICI treatments, the combination of PD-L1 and CTLA-4 with chemotherapy had the highest risk of immune-related adverse events, with severe cases like myocarditis and pneumonitis showing notably high fatality rates, indicating the need for careful monitoring and management in patients receiving these therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Toxicity spectrum of immunotherapy in advanced lung cancer: A safety analysis from clinical trials and a pharmacovigilance system. Yan, YD., Zhao, Y., Zhang, C., et al.[2022]

Vaccination with immature dendritic cells (iDCs) significantly reduced tumor growth and prolonged survival in mouse models of pancreatic adenocarcinoma, demonstrating their potential as a therapeutic strategy to enhance antitumor immunity.

Combining iDC-vaccination with the chemotherapy regimen FOLFIRINOX further increased survival in mice, suggesting that this combination could be a promising treatment option for patients with pancreatic adenocarcinoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dendritic cell-based vaccination: powerful resources of immature dendritic cells against pancreatic adenocarcinoma. Collignon, A., Silvy, F., Robert, S., et al.[2021]

In a study involving 93 patients with metastatic pancreatic cancer, combining GVAX vaccine and cyclophosphamide with nivolumab (Arm A) did not significantly improve overall survival compared to the same treatment without nivolumab (Arm B), with median survival times of 5.9 and 6.1 months, respectively.

Despite not meeting the primary endpoint, Arm A showed some objective tumor responses and beneficial immunologic changes in long-term survivors, such as increased CD8+ T cells, suggesting potential for immune modulation even if overall survival was similar to standard therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evaluation of Cyclophosphamide/GVAX Pancreas Followed by Listeria-Mesothelin (CRS-207) with or without Nivolumab in Patients with Pancreatic Cancer. Tsujikawa, T., Crocenzi, T., Durham, JN., et al.[2023]

Citations

1. investor.agenusbio.com investor.agenusbio.com/news/news-details/2025/Agenus-Presents-Data-at-ASCO-GI-Demonstrating-Impact-of-BOTBAL-in-Colorectal-Cancer-Across-Neoadjuvant-and-Advanced-Disease/default.aspx

Agenus Presents Data at ASCO GI Demonstrating Impact ... Data from five presentations underscore the transformative potential of BOT/BAL across multiple lines of therapy in colorectal cancer.

2. nature.com nature.com/articles/s41591-024-03083-7

Botensilimab plus balstilimab in relapsed/refractory ... Median follow-up was 6.3 months (range, 0.7–42.6 months), and the median duration of response (DOR) was not reached (NR; 95% CI, 4.2 months–NR).

3. oncodaily.com oncodaily.com/oncolibrary/botensilimab-balstilimab-esmo-gi-2025

Botensilimab and Balstilimab Show Durable Survival in ... Botensilimab plus balstilimab delivers 21-month overall survival in MSS colorectal cancer, per updated Phase 1b data at ESMO GI 2025.

4. cancernetwork.com cancernetwork.com/view/botensilimab-balstilimab-elicits-sustained-efficacy-in-mss-metastatic-crc

Botensilimab/Balstilimab Elicits Sustained Efficacy in MSS ... References · Agenus' BOT/BAL achieves 42% two-year survival in refractory MSS CRC, advances toward registration with FDA alignment on phase 3.

5. onclive.com onclive.com/view/dr-schlechter-on-updated-data-for-botensilimab-plus-balstilimab-in-mss-mcrc

Dr Schlechter on Updated Data for Botensilimab Plus ... Median progression-free survival (PFS) was 4.0 months (95% CI, 2.8-4.1), and the median overall survival (OS) reached 20.9 months (95% CI, 16.2- ...

6. ascopubs.org ascopubs.org/doi/10.1200/JCO.2025.43.4_suppl.23

Preliminary results from a randomized, open-label, phase 2 ... Here we present preliminary data from a randomized, open-label, phase 2 study in patients (pts) with MSS mCRC NLM treated with BOT ± BAL (anti-PD−1; NCT ...

7. clinicaltrials.gov clinicaltrials.gov/study/NCT07128355

Botensilimab, Balstilimab, and SBRT in Colorectal Cancer Members are chosen based on the scientific skills and knowledge needed to monitor the particular trial. Also called a data safety and monitoring board, or DSMB.

8. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/38871975/

Botensilimab plus balstilimab in relapsed/refractory ... - PubMed Botensilimab plus balstilimab in relapsed/refractory microsatellite stable metastatic colorectal cancer: a phase 1 trial. Nat Med. 2024 Sep ...