KRAS Vaccine + Immunotherapy for Lung Cancer

Overseen By Kristen Marrone, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Must not be taking: Corticosteroids, Chemotherapy, Immunotherapy, others

Disqualifiers: Autoimmune disease, Brain metastases, others

Stay on Your Current Meds You can continue your current medications while participating

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

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: Unknown

Duration: Up to 29 days

12 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial tests a special vaccine combined with immune-boosting substances and two drugs in advanced lung cancer patients with specific genetic mutations. The goal is to teach the immune system to attack the cancer cells more effectively.

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

The trial protocol does not specify if you need to stop taking your current medications. However, certain treatments like systemic corticosteroids, chemotherapy, and investigational drugs are not allowed shortly before starting the trial. It's best to discuss your specific medications with the trial team.

What data supports the effectiveness of the KRAS Vaccine + Immunotherapy treatment for lung cancer?

Research shows that a multipeptide KRAS vaccine significantly reduced tumor number and burden by over 80% in a mouse model of KRAS-driven lung cancer, indicating its potential effectiveness in preventing KRAS-driven cancers. ^{1 2 3 4 5}

Is the KRAS vaccine combined with immunotherapy safe for humans?

The KRAS vaccine has been tested in mice and shown to be safe, with a strong immune response and minimal side effects. Additionally, a similar mRNA vaccine targeting KRAS mutations in humans was found to be safe, with no serious side effects reported in a small trial. ^{1 3 4 6 7}

How is the KRAS Vaccine + Immunotherapy treatment for lung cancer different from other treatments?

This treatment is unique because it combines a vaccine targeting KRAS mutations with immunotherapy drugs (Ipilimumab and Nivolumab) to enhance the immune system's ability to fight lung cancer, specifically targeting a mutation that is often difficult to treat with existing therapies. ^{1 2 3 4 8}

Research Team

Kristen Marrone, MD

Principal Investigator

Johns Hopkins University

Eligibility Criteria

Adults with advanced, inoperable KRAS-mutated non-small cell lung cancer (NSCLC) who haven't had prior treatment for this stage. Participants must have tumors that can be biopsied, good physical health (ECOG 0 or 1), and proper organ function. Women of childbearing age and sexually active men must agree to contraception use.

Inclusion Criteria

Women who could become pregnant must have a negative pregnancy test. If the test is positive or uncertain, an ultrasound must be done to confirm if the person is pregnant before joining the study.

My lung cancer is advanced and has not been treated yet.

My tumor has one of the six specific KRAS mutations.

Exclusion Criteria

I have been diagnosed with an immune system disorder.

I haven't had cancer or blood disorders in the last 5 years, except for certain low-risk types.

My brain metastases are treated, I'm symptom-free, and it's been 2 weeks since my last therapy.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive the KRAS peptide vaccine with poly-ICLC adjuvant in combination with nivolumab and ipilimumab

Up to 29 days

Multiple visits for administration and monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 4 years

Long-term monitoring

Participants are monitored for progression free survival and T cell response

Up to 2 years

Treatment Details

Interventions

• Ipilimumab
• Nivolumab
• Pooled Mutant KRAS-Targeted Long Peptide Vaccine

Trial Overview The trial is testing a new vaccine targeting specific KRAS mutations in NSCLC combined with the immune checkpoint inhibitors nivolumab and ipilimumab. It aims to assess safety, feasibility, and how well it prevents disease progression.

Participant Groups

Group I: Patients With NSCLC Experimental Treatment 1 Intervention

All participants will receive the intervention.

Ipilimumab is already approved in United States, European Union for the following indications:

Approved in United States as Yervoy for:

• Advanced melanoma
• Stage III unresectable melanoma
• Stage IV metastatic melanoma

Approved in European Union as Yervoy for:

• Advanced melanoma
• Stage III unresectable melanoma
• Stage IV metastatic melanoma

Who Is Running the Clinical Trial?

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Lead Sponsor

Trials

578

Recruited

33,600+

Findings from Research

The multi-peptide vaccine Emut Vax effectively prevented the development of lung tumors driven by common EGFR mutations in mouse models, indicating its potential as a preventive treatment for EGFR mutation-positive lung cancer.

Emut Vax not only enhanced Th1 immune responses in the tumor microenvironment but also reduced the number of suppressive T regulatory cells, suggesting a robust immune modulation that could improve anti-tumor efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Precision immunointerception of EGFR-driven tumorigenesis for lung cancer prevention. Pan, J., Xiong, D., Zhang, Q., et al.[2023]

Vaccines designed to enhance tumor antigen recognition in non-small cell lung cancer patients show promising results, including prolonged stable disease and tumor shrinkage, with no reported toxicity.

Specific vaccines such as LBLP25, TGF-beta2 antisense gene vaccine, and GVAX have demonstrated potential benefits that warrant further Phase III clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A review of vaccine clinical trials for non-small cell lung cancer. Nemunaitis, J., Nemunaitis, J.[2019]

The multipeptide vaccine targeting KRAS mutations demonstrated over 80% reduction in tumor number and burden in a mouse model, indicating strong antitumor efficacy before the mutant KRAS protein was activated.

The vaccine elicited a robust immune response characterized by Th1 cytokine secretion, suggesting it could be an effective preventive strategy against KRAS-driven lung cancer and potentially other cancers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immunoprevention of KRAS-driven lung adenocarcinoma by a multipeptide vaccine. Pan, J., Zhang, Q., Sei, S., et al.[2019]

Del19 mutations of the EGFR gene are prevalent in about 40% of Chinese lung adenocarcinoma patients and can be effectively targeted for immunotherapy, as they are presented by multiple HLA Class I and II molecules.

Patients with Del19 EGFR mutations show significantly higher immune responses to the wild type EGFR protein compared to those with other mutations, indicating the potential for developing effective cancer vaccines based on these mutations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immunogenicity of Del19 EGFR mutations in Chinese patients affected by lung adenocarcinoma. Pan, D., Zhou, D., Cai, W., et al.[2020]

In this study, bioinformatics tools were effectively used to identify two promising mimotopes (164-D and 224-D) from mutated KRAS that can stimulate strong immune responses, which could lead to new immunotherapies for cancers like pancreatic and colorectal cancer.

The selected mimotopes showed the ability to induce specific cytokine responses and elevated IgG titers in mice, suggesting their potential as effective candidates for future cancer vaccines targeting KRAS mutations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

In silico-guided sequence modifications of K-ras epitopes improve immunological outcome against G12V and G13D mutant KRAS antigens. Ng, AWR., Tan, PJ., Hoo, WPY., et al.[2022]

Osimertinib, a third-generation EGFR-TKI, is effective against non-small cell lung cancer (NSCLC) with the EGFR T790M mutation, but most patients develop resistance within a year, often due to additional mutations like C797S.

This study identified a specific peptide from the EGFR T790M/C797S mutation that can stimulate cytotoxic T cell responses, suggesting that immunotherapy targeting this neoantigen could be a promising new treatment for NSCLC patients who have developed resistance to osimertinib.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy of immunotherapy targeting the neoantigen derived from epidermal growth factor receptor T790M/C797S mutation in non-small cell lung cancer. Akazawa, Y., Saito, Y., Yoshikawa, T., et al.[2022]

The personalized mRNA vaccine targeting neoantigens in patients with metastatic gastrointestinal cancer was found to be safe and successfully elicited specific T cell responses against previously undetected neoepitopes.

Despite the safety and immune response generated by the vaccine, no objective clinical responses were observed in the four patients treated, suggesting the need for further research, possibly in combination with other therapies like checkpoint inhibitors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

mRNA vaccine-induced neoantigen-specific T cell immunity in patients with gastrointestinal cancer. Cafri, G., Gartner, JJ., Zaks, T., et al.[2021]

The combination of a multi-peptide Kras vaccine with avasimibe, an ACAT1 inhibitor, significantly improved anti-cancer efficacy in mouse models of lung cancer by enhancing CD8+ T cell infiltration and reducing regulatory T cells in the tumor microenvironment.

This treatment approach not only increased the activation of CD8+ T cells but also modulated cholesterol metabolism specifically in T cells, suggesting a novel immunoprevention strategy for targeting mutant Kras in lung cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Potentiation of Kras peptide cancer vaccine by avasimibe, a cholesterol modulator. Pan, J., Zhang, Q., Palen, K., et al.[2021]

References

1. Switzerland pubmed.ncbi.nlm.nih.gov

Precision immunointerception of EGFR-driven tumorigenesis for lung cancer prevention. [2023]

2. England pubmed.ncbi.nlm.nih.gov

A review of vaccine clinical trials for non-small cell lung cancer. [2019]

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

Immunoprevention of KRAS-driven lung adenocarcinoma by a multipeptide vaccine. [2019]

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

Immunogenicity of Del19 EGFR mutations in Chinese patients affected by lung adenocarcinoma. [2020]

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

In silico-guided sequence modifications of K-ras epitopes improve immunological outcome against G12V and G13D mutant KRAS antigens. [2022]

6. England pubmed.ncbi.nlm.nih.gov

Efficacy of immunotherapy targeting the neoantigen derived from epidermal growth factor receptor T790M/C797S mutation in non-small cell lung cancer. [2022]

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

mRNA vaccine-induced neoantigen-specific T cell immunity in patients with gastrointestinal cancer. [2021]

8. Netherlands pubmed.ncbi.nlm.nih.gov

Potentiation of Kras peptide cancer vaccine by avasimibe, a cholesterol modulator. [2021]