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

Trial Summary

What is the purpose of this trial?

Phase 1b study evaluating the efficacy and immune response to a synthetic long peptide mutant KRAS vaccine (SPL mKRASvax) combined with Balstilimab and Botensilimab for unresectable or metastatic mismatch repair-proficient (MMR-p) colorectal cancer (mCRC) or unresectable or metastatic MMR-p pancreatic ductal adenocarcinoma (PDAC) patients with measurable disease following first-line chemotherapy.

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.

What data supports the effectiveness of the KRAS Vaccine Combo treatment for colorectal and pancreatic cancer?

Research shows that vaccines targeting KRAS mutations, which are common in pancreatic cancer, can trigger strong immune responses and have shown promising results in early studies. Additionally, dendritic cell-based vaccines have been effective in reducing tumor growth and increasing survival in pancreatic cancer models, suggesting potential benefits when combined with other treatments. ^{1 2 3 4 5}

Is the KRAS Vaccine Combo generally safe for humans?

The safety of treatments like the KRAS Vaccine Combo, which includes immune checkpoint inhibitors, has been studied in various cancers. These treatments can cause immune-related side effects, but the specific safety profile for the KRAS Vaccine Combo in colorectal and pancreatic cancer is not detailed in the available research. ^{6 7 8 9 10}

What makes the KRAS Vaccine Combo treatment unique for colorectal and pancreatic cancer?

The KRAS Vaccine Combo treatment is unique because it targets specific mutations in the KRAS gene, which are common in colorectal and pancreatic cancers, using a vaccine approach combined with immune checkpoint inhibitors. This combination aims to enhance the body's immune response against the cancer, potentially overcoming the limitations of current treatments that have limited efficacy in these cancers. ^{2 3 4 11 12}

Research Team

Nilofer Azad, MD

Principal Investigator

SKCCC Johns Hopkins Medical Institution

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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

Findings from Research

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]

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]

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]

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]

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]

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 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]

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]

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]

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]

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]

References

1. United States 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. [2023]

2. United States pubmed.ncbi.nlm.nih.gov

Dendritic cell-based vaccination: powerful resources of immature dendritic cells against pancreatic adenocarcinoma. [2021]

3. United States pubmed.ncbi.nlm.nih.gov

Targeting mutated K-ras in pancreatic adenocarcinoma using an adjuvant vaccine. [2020]

4. England pubmed.ncbi.nlm.nih.gov

Cancer vaccines: Targeting KRAS-driven cancers. [2021]

5. United States 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. [2019]

6. Switzerland pubmed.ncbi.nlm.nih.gov

Pancreatic adverse events of immune checkpoint inhibitors therapy for solid cancer patients: a systematic review and meta-analysis. [2023]

7. England 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. [2023]

8. China pubmed.ncbi.nlm.nih.gov

Analysis of characteristics and predictive factors of immune checkpoint inhibitor-related adverse events. [2021]

9. Germany pubmed.ncbi.nlm.nih.gov

Predictors of immune checkpoint inhibitor-related adverse events in older patients with lung cancer: a prospective real-world analysis. [2023]

10. England pubmed.ncbi.nlm.nih.gov

Toxicity spectrum of immunotherapy in advanced lung cancer: A safety analysis from clinical trials and a pharmacovigilance system. [2022]

11. England pubmed.ncbi.nlm.nih.gov

Vaccines and immune checkpoint inhibitors: a promising combination strategy in gastrointestinal cancers. [2022]

12. Egypt 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. [2021]