Cancer Vaccines for Lynch Syndrome

Recruiting in Palo Alto (17 mi)

+17 other locations

Overseen by Ajay Bansal

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 2

Recruiting

Sponsor: National Cancer Institute (NCI)

Must not be taking: Corticosteroids, Immunosuppressants, others

Disqualifiers: Immunodeficiency, HIV, Hepatitis, others

Prior Safety Data

Trial Summary

What is the purpose of this trial?

This trial tests a vaccine and an immune booster to prevent cancer in people with Lynch syndrome. The vaccine teaches the body to fight cancer, and the booster makes this process stronger. Vaccines have shown robust potential for preventing Lynch syndrome cancers.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot be on certain immunosuppressive drugs or other investigational agents. It's best to discuss your specific medications with the study team.

What data supports the effectiveness of the treatment for Lynch Syndrome?

Research shows that the components of the Tri-Ad5 vaccine, which targets specific proteins found in various tumors, can activate immune cells in both lab and animal studies. This suggests potential for the vaccine to help the immune system fight cancer, as seen in other types of cancer like colorectal cancer. ^{1 2 3 4 5}

Is the cancer vaccine for Lynch Syndrome safe for humans?

The cancer vaccine using adenoviral vectors, like Tri-Ad5, has been tested in humans and generally shows a good safety profile, with most side effects being mild and temporary. However, early versions of adenoviral vectors have caused serious immune reactions, but newer versions have improved safety. In a study, no severe side effects were observed, and only one temporary serious side effect (diarrhea) was reported, which resolved without treatment. ^{1 2 4 6 7}

What makes the Tri-Ad5 cancer vaccine treatment unique for Lynch Syndrome?

The Tri-Ad5 cancer vaccine is unique because it targets three different tumor-associated antigens (proteins found on cancer cells) using a modified adenovirus to stimulate the immune system, potentially offering a novel approach for treating Lynch Syndrome, which currently lacks standard treatment options. ^{1 2 4 5 8}

Research Team

Ajay Bansal

Principal Investigator

University of Kansas

Eligibility Criteria

This trial is for adults with Lynch syndrome who've had adenomas, advanced adenomas, or colon cancer. They must be at least 6 months post any cancer treatment and have part of their colon/rectum intact. Participants need normal blood counts and organ function tests, agree to contraception use, and space out COVID vaccines around the study timeline. Exclusions include untreated blood clots, recent immunosuppressants use, certain infections like HIV/HBV/HCV with specific conditions, pregnancy/breastfeeding women, history of severe vaccine allergies.

Inclusion Criteria

Your creatinine levels are within the normal range set by the hospital.

You have a white blood cell count of at least 3,000 per microliter.

It has been over 6 months since my last cancer treatment.

Exclusion Criteria

I have had an organ transplant or have a condition that weakens my immune system.

I have HIV with a CD4 count under 540, or I have hepatitis B or C.

Uncontrolled intercurrent illness or psychiatric illness/social situations that would limit compliance with study requirements

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Safety Phase I

Participants receive Tri-Ad5 subcutaneously at weeks 0, 4, 8, and 52. Participants also undergo standard of care colonoscopy with biopsy at baseline, at 52 weeks and 104 weeks.

104 weeks

4 visits (in-person) for vaccination, 3 visits (in-person) for colonoscopy

Safety Phase II

Participants receive Tri-Ad5 and N-803 subcutaneously at weeks 0, 4, 8, and 52. Participants also undergo standard of care colonoscopy with biopsy at baseline, 52 weeks and 104 weeks.

104 weeks

4 visits (in-person) for vaccination, 3 visits (in-person) for colonoscopy

Randomized Control Phase

Participants are randomized into two arms: Arm I receives Tri-Ad5 and N-803, Arm II receives placebo. Both arms undergo standard of care colonoscopy with biopsy at baseline, 52 weeks, and 104 weeks.

104 weeks

4 visits (in-person) for vaccination, 3 visits (in-person) for colonoscopy

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Adenovirus 5 CEA/MUC1/Brachyury Vaccine Tri-Ad5 (Cancer Vaccine)
• Nogapendekin Alfa (Immunomodulator)
• Placebo Administration (Placebo)

Trial Overview The trial is testing a combination of Tri-Ad5 vaccine (with three substances targeting precancer/cancer cells) and N-803 (an immune enhancer), aiming to prevent cancers in those with Lynch syndrome. The idea is that this combo might train the immune system to fight off potential cancer cells more effectively.

Participant Groups

Group I: Safety phase II (Tri-Ad5 , N-803) Experimental Treatment 6 Interventions

Participants receive Tri-Ad5 SC and N-803 SC at weeks 0, 4, 8, and 52. Participants also undergo SOC colonoscopy with biopsy at baseline and at 52 weeks and 104 weeks. Participants undergo blood sample collection throughout the study.

Group II: Safety phase I (Tri-Ad5) Experimental Treatment 5 Interventions

Participants receive Tri-Ad5 SC at weeks 0, 4, 8, and 52. Participants also undergo SOC colonoscopy with biopsy at baseline and at 52 weeks and 104 weeks. Participants undergo blood sample collection throughout the study.

Group III: Arm I (Tri-Ad5, N-803) Experimental Treatment 6 Interventions

Participants receive Tri-Ad5 SC and N-803 SC at weeks 0, 4, 8, and 52. Participants also undergo SOC colonoscopy with biopsy at baseline and at 52 and 104 weeks. Participants undergo blood sample collection throughout the study.

Group IV: Arm II (placebo) Placebo Group 5 Interventions

Participants receive placebo SC at weeks 0, 4, 8, and 52. Participants also undergo SOC colonoscopy with biopsy at baseline and at 52 and 104 weeks. Participants undergo blood sample collection throughout the study.

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Dr. Douglas R. Lowy

National Cancer Institute (NCI)

Chief Executive Officer since 2023

MD from New York University School of Medicine

Dr. Monica Bertagnolli

National Cancer Institute (NCI)

Chief Medical Officer since 2022

MD from Harvard Medical School

Findings from Research

The novel adenovirus vector platform (Ad5 [E1-, E2b-]) shows promise in reducing immune response to the vector itself, allowing for more effective delivery of tumor-associated antigens (TAAs) like CEA, brachyury, and MUC1 in cancer vaccines.

The combination vaccine (Tri-Ad5) targeting multiple TAAs demonstrated the ability to activate specific T cell responses without significant competition between the antigens, suggesting it could be an effective approach for treating diverse human tumors in future clinical studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The generation and analyses of a novel combination of recombinant adenovirus vaccines targeting three tumor antigens as an immunotherapeutic. Gabitzsch, ES., Tsang, KY., Palena, C., et al.[2018]

The Ad5 PSA/MUC-1/brachyury vaccine targeting metastatic castration-resistant prostate cancer (mCRPC) was found to be safe and well-tolerated, with no severe treatment-related adverse events reported in a trial involving 18 patients.

The vaccine demonstrated clinical activity, with one patient achieving a partial response and five showing a decline in PSA levels, indicating potential effectiveness in generating an immune response against tumor-associated antigens.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I study of a multitargeted recombinant Ad5 PSA/MUC-1/brachyury-based immunotherapy vaccine in patients with metastatic castration-resistant prostate cancer (mCRPC). Bilusic, M., McMahon, S., Madan, RA., et al.[2021]

The GI-6301 vaccine, which targets the brachyury protein, was shown to be safe and capable of activating T-cell immune responses in most patients, even those who had undergone extensive prior treatments, in a phase I trial with 34 participants.

Two patients with chordoma experienced disease control, and one colorectal cancer patient showed stable disease for over a year, indicating potential clinical activity of the vaccine and supporting further investigation in phase II trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I Trial of a Yeast-Based Therapeutic Cancer Vaccine (GI-6301) Targeting the Transcription Factor Brachyury. Heery, CR., Singh, BH., Rauckhorst, M., et al.[2022]

The MVA-brachyury-TRICOM vaccine, designed to target the brachyury transcription factor associated with cancer progression, was safely administered to 38 advanced cancer patients without any dose-limiting toxicities, indicating a favorable safety profile.

The vaccine successfully activated brachyury-specific T-cell responses in most patients, suggesting its potential efficacy in enhancing the immune response against tumors that express brachyury.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I Study of a Poxviral TRICOM-Based Vaccine Directed Against the Transcription Factor Brachyury. Heery, CR., Palena, C., McMahon, S., et al.[2019]

The DNA electroporation and adenovirus-based genetic vaccine effectively triggered an immune response against the human carcinoembryonic antigen (CEA) in mouse models of colorectal cancer, demonstrating significant antitumor effects.

This study suggests that targeting CEA with genetic vaccines could be a promising strategy for treating gut tumors, as the models used closely mimic human colorectal cancer, allowing for better evaluation of vaccine efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A therapeutic cancer vaccine targeting carcinoembryonic antigen in intestinal carcinomas. Mori, F., Giannetti, P., Peruzzi, D., et al.[2010]

The study demonstrates that MUC1 is essential for the effectiveness of colorectal cancer stem cell (CCSC) vaccines, as MUC1 knockdown reduced the vaccine's anti-tumor efficacy, while MUC1 overexpression enhanced it.

CCSC vaccines significantly reduced tumor growth by targeting CCSCs, increasing the activity of immune cells like NK cells, and promoting the release of key immune factors, indicating a robust immune response against colorectal cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Colorectal cancer stem cell vaccine with high expression of MUC1 serves as a novel prophylactic vaccine for colorectal cancer. Guo, M., Luo, B., Pan, M., et al.[2021]

The latest generation of high-capacity adenoviral vectors has a significantly improved safety profile compared to earlier versions, as they are devoid of viral genes that cause inflammatory responses and toxicity, leading to more prolonged therapeutic gene expression.

Despite their advancements, high-capacity adenoviral vectors can still cause transient toxic effects, and while there is a low risk of malignancy associated with these vectors, integrating adenoviral vectors pose a higher risk due to their random integration into target genomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Biosafety of adenoviral vectors. Chuah, MK., Collen, D., VandenDriessche, T.[2019]

The study developed a dendritic cell-based vaccine targeting the tumor-associated antigen MUC4, which is overexpressed in various cancers, showing promise for broad applicability in cancer immunotherapy.

In vitro tests demonstrated that the vaccine effectively primed lymphocytes to generate strong cytotoxic responses against MUC4-expressing cells, indicating its potential efficacy in treating MUC4-associated tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dendritic cells expressing a combined PADRE/MUC4-derived polyepitope DNA vaccine induce multiple cytotoxic T-cell responses. Wei, J., Gao, W., Wu, J., et al.[2019]

References

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

The generation and analyses of a novel combination of recombinant adenovirus vaccines targeting three tumor antigens as an immunotherapeutic. [2018]

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

Phase I study of a multitargeted recombinant Ad5 PSA/MUC-1/brachyury-based immunotherapy vaccine in patients with metastatic castration-resistant prostate cancer (mCRPC). [2021]

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

Phase I Trial of a Yeast-Based Therapeutic Cancer Vaccine (GI-6301) Targeting the Transcription Factor Brachyury. [2022]

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

Phase I Study of a Poxviral TRICOM-Based Vaccine Directed Against the Transcription Factor Brachyury. [2019]

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

A therapeutic cancer vaccine targeting carcinoembryonic antigen in intestinal carcinomas. [2010]

6. Netherlands pubmed.ncbi.nlm.nih.gov

Colorectal cancer stem cell vaccine with high expression of MUC1 serves as a novel prophylactic vaccine for colorectal cancer. [2021]

7. United Arab Emirates pubmed.ncbi.nlm.nih.gov

Biosafety of adenoviral vectors. [2019]

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

Dendritic cells expressing a combined PADRE/MUC4-derived polyepitope DNA vaccine induce multiple cytotoxic T-cell responses. [2019]