KRAS Vaccine + Immunotherapy for Lung Cancer

Overseen By Shakila Rajack

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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to test a new combination of treatments for individuals with advanced lung cancer that cannot be surgically removed. Researchers seek to determine if a KRAS peptide vaccine, combined with two immunotherapy drugs—nivolumab (Opdivo) and ipilimumab (Yervoy)—is safe and feasible. The study targets patients whose lung tumors have specific KRAS gene mutations. A suitable candidate for this trial would have advanced lung cancer that has not yet been treated at this stage and possesses one of the identified KRAS mutations. 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 treatment combination.

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.

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

Research shows that using nivolumab and ipilimumab together is generally safe for treating advanced non-small cell lung cancer (NSCLC). Studies have found that the safety profile of these combined drugs is similar to other treatments. However, some side effects can occur. Serious side effects, such as lung infections (pneumonia), trouble breathing, and respiratory failure, were reported in about 2% of patients.

The KRAS peptide vaccine remains in early testing to assess its safety. Early trials focus on determining the safety of this vaccine when used with other drugs. While detailed safety information is still being collected, the current phase of the trial primarily evaluates how well patients tolerate the treatment.

In summary, while safety data exists for nivolumab and ipilimumab, the KRAS vaccine continues to be closely monitored to ensure its safety for patients. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Unlike the standard treatments for non-small cell lung cancer (NSCLC), which often involve chemotherapy or targeted drugs, this innovative approach combines a KRAS-targeted vaccine with immunotherapy. The KRAS vaccine targets specific mutations in the cancer cells, essentially teaching the immune system to recognize and attack them. This strategy is paired with ipilimumab and nivolumab, two powerful immunotherapy drugs that boost the immune system's response. Researchers are excited because this combination might enhance the immune system's ability to fight cancer more effectively than existing treatments, offering new hope for patients with difficult-to-treat KRAS mutations.

What evidence suggests that this trial's treatments could be effective for lung cancer?

Research has shown that using nivolumab and ipilimumab together can greatly benefit patients with advanced non-small-cell lung cancer (NSCLC). In some studies, 42% of patients who received nivolumab remained alive after treatment, surpassing the results from chemotherapy. This drug combination has also demonstrated a 49% ongoing response rate at two years, significantly higher than standard treatments.

In this trial, all participants will receive a combination of the KRAS-targeted vaccine and immunotherapy. Early results suggest that the KRAS-targeted vaccine may shrink tumors by more than 80% when used with other treatments. This vaccine is designed to teach the immune system to specifically attack cancer cells with KRAS mutations. Overall, these treatments show promise for improving outcomes in patients with certain genetic types of lung cancer. ^{4 6 7 8 9}

Who Is on the Research Team?

Kristen Marrone, MD

Principal Investigator

Johns Hopkins University

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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 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]

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]

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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9937094/

Five-Year Survival Outcomes With Nivolumab Plus Ipilimumab ... Patients with metastatic non–small-cell lung cancer (mNSCLC) have historically had a 5-year survival rate of only 7%, but more recently, immune check point ...

2. opdivohcp.com opdivohcp.com/efficacy/nsclc/opdivo-yervoy

OPDIVO® (nivolumab) + YERVOY® (ipilimumab) Efficacy ... In NSCLC patients receiving OPDIVO 3 mg/kg every 2 weeks with YERVOY 1 mg/kg every 6 weeks, immune-mediated pneumonitis occurred in 9% (50/576) of patients, ...

3. nejm.org nejm.org/doi/full/10.1056/NEJMoa1910231

Nivolumab plus Ipilimumab in Advanced Non–Small-Cell ... At 2 years, the rate of ongoing response was 49% with nivolumab plus ipilimumab, as compared with 11% with chemotherapy. The safety of nivolumab plus ipilimumab ...

4. ejcancer.com ejcancer.com/article/S0959-8049(24)00952-3/fulltext

Five-year outcomes with first-line nivolumab plus ... Patients who discontinued nivolumab plus ipilimumab with chemotherapy due to treatment-related adverse events had a 5-year OS rate of 37%. Five- ...

5. jto.org jto.org/article/S1556-0864(24)02355-4/fulltext

Long-Term Survival Outcomes With First-Line Nivolumab ... In patients with squamous NSCLC, median OS was 16.2 versus 8.2 months with nivolumab plus ipilimumab with or without chemotherapy versus ...

6. opdivohcp.com opdivohcp.com/safety/nsclc/opdivo-yervoy

OPDIVO® (nivolumab) + YERVOY® (ipilimumab) Safety ... View the selected safety profile for OPDIVO® (nivolumab) + YERVOY® (ipilimumab) in metastatic non-small lung cancer (mNSCLC). Please see Indications and ...

7. ema.europa.eu ema.europa.eu/en/medicines/human/EPAR/yervoy

Yervoy | European Medicines Agency (EMA) Yervoy is a cancer medicine used to treat the following: The medicine is used in adults; for melanoma it is also used in adolescents from 12 years of age.

8. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/38240151/

Real-world safety of first-line immuno-oncology ... These results show that in a real-world setting, NIVO + IPI-based regimens have similar safety to other IO + chemotherapy combinations when used as a first ...

9. opdivo.com opdivo.com/nsclc/clinical-trial-results/advanced-pd-l1-positive-immunotherapy-combination

Non-small cell lung cancer (NSCLC) OPDIVO (nivolumab) is a prescription medicine used in combination with YERVOY (ipilimumab) as a first treatment for adults with a type of advanced stage lung ...