HPV Specific T Cells + Immunotherapy for Cancer

(HESTIA Trial)

Overseen By Carlos Ramos, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Baylor College of Medicine

Must not be taking: Tumor vaccines, T cell antibodies

Disqualifiers: HIV, Severe infection, Pregnancy, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: 6 weeks

32 Participants Needed

Trial Summary

What is the purpose of this trial?

Subjects have a type of cancer that has been associated with an infection with a virus called human papilloma virus (HPV). The cancer has come back, has not gone away after standard treatment or the subject cannot receive standard treatment. This is a research study using special immune system cells called HPVST cells, a new experimental treatment. Investigators want to find out if they can use this type of treatment in patients with HPV-cancers. They have discovered a way to grow large number of HPV-specific T cells from the blood of patients with HPV-cancers. They want to see if these special white blood cells, called HPVST cells, that will have been trained to kill HPV infected cells can survive in the blood and affect the tumor. They will also see if they can make the T cells more active against the HPV-cancers by engineering them to be resistant to the TGF-beta chemical that these HPV-cancers produce. They will grow these HPVST cells from the patient's blood. The purpose of this study is to find the biggest dose of HPVSTs that is safe, to see how long they last in the body, to learn what the side effects are and to see if the HPVSTs will help people with HPV associated cancers. If the treatment with HPVST cells alone proves safe (Group A), additional group of patients (Group B) will receive Nivolumab in addition to HPVST cells in a lymphodepleted environment. Nivolumab is an antibody therapy that helps T cells control the tumor and it is FDA approved for the treatment of certain types of cancers, including Hodgkin's lymphoma. Lymphodepletion will decrease the level of circulating T cells prior to infusion of HPVST cells, thereby giving them room to expand. The purpose of this part of the study is to find out if TGF-beta resistant HPVST cells in combination with Nivolumab are safe, how long they last in the body and if they are more effective than HPVST cells alone in controlling the tumor.

Will I have to stop taking my current medications?

The trial protocol does not specify if you need to stop taking your current medications. However, you cannot participate if you are currently receiving any investigational agents or have received tumor vaccines or T cell antibodies in the past 4 weeks.

What data supports the effectiveness of this treatment for HPV-related cancers?

Research shows that T-cell therapies targeting HPV-specific antigens, like E7, have shown promise in treating HPV-related cancers by specifically attacking cancer cells without harming healthy tissues. Additionally, immune checkpoint blockade therapies, which help the immune system recognize and attack cancer cells, are already approved for certain HPV-associated cancers, indicating potential effectiveness of similar treatments. ^{1 2 3 4 5}

Is the HPV Specific T Cells + Immunotherapy treatment generally safe for humans?

The treatment involving engineered T cells, like HPV Specific T Cells, has shown no significant safety concerns in preclinical models, with no tumor or gene-related issues observed. However, cancer immunotherapies, including those using T cells, can cause immune-related side effects, such as autoimmune reactions, which need careful management. ^{6 7 8 9 10}

How does the HPV Specific T Cells + Immunotherapy treatment differ from other treatments for HPV-associated cancers?

This treatment is unique because it uses HPV-specific T cells, which are engineered to target HPV proteins consistently expressed in tumor cells, combined with immunotherapy to enhance the body's immune response against cancer. Unlike traditional treatments, this approach specifically targets viral antigens and may reduce the risk of immune-related side effects. ^{3 4 11 12 13}

Research Team

Carlos Ramos, MD

Principal Investigator

Baylor College of Medicine

Eligibility Criteria

This trial is for adults over 18 with recurrent or persistent HPV-associated cancers after standard treatment, or those who can't receive standard therapy. Participants need a Karnofsky score of at least 50%, indicating they are able to perform daily activities. They must have a life expectancy of more than 6 weeks, adequate organ function, and agree to use effective birth control. People with HIV, current investigational treatments, severe infections, or who are pregnant cannot join.

Inclusion Criteria

I am 18 years old or older.

I am able to care for myself but cannot do normal activities or work.

You are already undergoing treatment for your condition.

Exclusion Criteria

I am not currently on experimental drugs or had cancer vaccines or T cell treatments in the last 4 weeks.

Pregnancy or lactation.

I do not have a severe ongoing infection.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive HPV-specific T cells, with potential additional doses based on response; Group B may receive additional nivolumab and lymphodepletion

6 weeks

Initial infusion on day 0, potential additional doses based on response; Group B receives nivolumab every 2 weeks for 4 doses

Follow-up

Participants are monitored for safety and effectiveness after treatment, including blood draws and examinations

6 weeks

Treatment Details

Interventions

• Cytoxan
• Fludarabine
• HPV Specific T Cells
• Nivolumab

Trial Overview The study tests HPV-specific T cells (HPVST) designed to fight cancer by targeting the virus that causes it. The first group receives only these cells; if safe, another group will get them plus Nivolumab—an FDA-approved antibody—in a lymphodepleted state to potentially enhance effectiveness.

Participant Groups

Group I: Group B Experimental Treatment 4 Interventions

HPV Specific T Cells plus lymphodepletion (Cytoxan and Fludarabine) and nivolumab

Group II: Group A Experimental Treatment 1 Intervention

HPV Specific T Cells

Who Is Running the Clinical Trial?

Baylor College of Medicine

Lead Sponsor

Trials

1,044

Recruited

6,031,000+

Center for Cell and Gene Therapy, Baylor College of Medicine

Collaborator

Trials

114

Recruited

2,900+

The Methodist Hospital Research Institute

Collaborator

Trials

299

Recruited

82,500+

Findings from Research

A high-avidity T cell receptor (TCR) targeting the HPV-16 E7 antigen was identified from a cervical biopsy, showing strong potential for treating HPV+ cancers due to its ability to specifically recognize and kill cancer cells.

In mouse models, T cells engineered to express this TCR successfully regressed established HPV-16+ cervical cancer tumors, paving the way for a clinical trial to evaluate this TCR gene therapy in patients with metastatic HPV+ cancers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Engineered T cells targeting E7 mediate regression of human papillomavirus cancers in a murine model. Jin, BY., Campbell, TE., Draper, LM., et al.[2022]

A T-cell receptor therapy has shown early effectiveness in treating cancers associated with human papillomavirus (HPV), indicating a potential new approach for these types of cancers.

This therapy targets specific T-cells to fight HPV-linked cancers, suggesting a mechanism that could enhance the immune response against these tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

T-cell Receptor-Engineered T Cells Show Efficacy in HPV+ Carcinomas. [2021]

TCR gene transfer can successfully generate HPV16 specific CD4+ T helper cells, which are crucial for effective immunotherapy against HPV-related cancers, as demonstrated through functional assays involving interferon-γ secretion and cytokine production.

The study shows that these engineered T cells can recognize specific HPV16 antigens presented by MHC molecules, indicating a promising approach for enhancing T cell responses in patients with cervical cancer and other HPV16-induced malignancies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Generating HPV specific T helper cells for the treatment of HPV induced malignancies using TCR gene transfer. Scholten, KB., Turksma, AW., Ruizendaal, JJ., et al.[2021]

The TCRα-modified T cell product showed no signs of tumorigenic or mutagenic activity in vitro, indicating that the viral vectors used for its generation are safe and do not cause genetic damage.

In mouse models, the adoptive transfer of TCRα-engineered T cells did not disrupt normal body functions and showed no acute toxicity or harmful immune reactions, suggesting a favorable safety profile for potential clinical use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety evaluation of the mouse TCRα - transduced T cell product in preclinical models in vivo and in vitro. Kalinina, A., Bruter, A., Persiyantseva, N., et al.[2022]

Anti-CTLA4 and anti-PD1/PD-L1 immunotherapies represent a significant shift in cancer treatment by enhancing the immune system's ability to fight tumors rather than directly targeting the tumor cells themselves.

These immunotherapies can lead to unique immune-related adverse events due to the activation of the immune system against normal tissues, necessitating changes in clinical management to address potential autoimmune reactions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Management of adverse events associated with cancer immunotherapy]. Champiat, S., Michot, JM., Lambotte, O.[2019]

Engineered T cell therapies, like CAR T cells and TCR T cell therapies, have shown remarkable efficacy in treating certain blood cancers, highlighting their potential as a powerful tool in cancer immunotherapy.

However, these therapies also pose unique safety challenges, such as cytokine release syndrome and neurotoxicity, which require careful nonclinical safety assessments to ensure patient safety during development.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nonclinical safety assessment of engineered T cell therapies. Lebrec, H., Maier, CC., Maki, K., et al.[2022]

Cancer immunotherapies, particularly anti-CTLA4 and anti-PD1/PD-L1, are becoming more common in treatment regimens, leading to increased exposure of patients to immune-related adverse events (irAEs).

These immunotherapies can activate the immune system to fight tumors effectively, but they also have a unique toxicity profile that can cause autoimmune reactions, necessitating changes in clinical management practices to address these side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Management of adverse events associated with cancer immunotherapy]. Laparra, A., Champiat, S., Michot, JM., et al.[2021]

In a study of patients with metastatic cervical cancer, the most effective T cell responses were found to target mutated neoantigens and a cancer germline antigen, rather than the expected viral antigens from human papillomavirus (HPV).

The presence of T cells targeting both viral and nonviral antigens in the PD-1-expressing compartment indicates that blocking PD-1 could enhance the effectiveness of immunotherapy by activating a broader range of antitumor T cell responses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Landscape of immunogenic tumor antigens in successful immunotherapy of virally induced epithelial cancer. Stevanović, S., Pasetto, A., Helman, SR., et al.[2021]

T cell-mediated adoptive immunotherapy targeting HPV16 proteins E6 and E7 shows promise as a safe and effective treatment for HPV-related cancers, particularly through the generation of MHC class II-restricted T cells.

The study successfully isolated a TCR specific to HPV16-E7 from a patient with a complete response, demonstrating that TCR gene transfer can produce sufficient numbers of functional T cells that can recognize and respond to HPV-infected cells.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Isolation and Characterization of an HLA-DRB1*04-Restricted HPV16-E7 T Cell Receptor for Cancer Immunotherapy. Mercier-Letondal, P., Marton, C., Deschamps, M., et al.[2019]

References

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

Engineered T cells targeting E7 mediate regression of human papillomavirus cancers in a murine model. [2022]

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

T-cell Receptor-Engineered T Cells Show Efficacy in HPV+ Carcinomas. [2021]

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

Immunotherapy for HPV Malignancies. [2022]

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

Generating HPV specific T helper cells for the treatment of HPV induced malignancies using TCR gene transfer. [2021]

5. Switzerland pubmed.ncbi.nlm.nih.gov

Circulating Exhausted PD-1+CD39+ Helper CD4 T Cells Are Tumor-Antigen-Specific and Predict Response to PD-1/PD-L1 Axis Blockade. [2022]

6. France pubmed.ncbi.nlm.nih.gov

Safety evaluation of the mouse TCRα - transduced T cell product in preclinical models in vivo and in vitro. [2022]

7. France pubmed.ncbi.nlm.nih.gov

[Management of adverse events associated with cancer immunotherapy]. [2019]

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

Nonclinical safety assessment of engineered T cell therapies. [2022]

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

Toxicities Associated With Adoptive T-Cell Transfer for Cancer. [2019]

10. France pubmed.ncbi.nlm.nih.gov

[Management of adverse events associated with cancer immunotherapy]. [2021]

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

Landscape of immunogenic tumor antigens in successful immunotherapy of virally induced epithelial cancer. [2021]

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

Isolation and Characterization of an HLA-DRB1*04-Restricted HPV16-E7 T Cell Receptor for Cancer Immunotherapy. [2019]

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

Human papillomavirus type 33 E7 peptides presented by HLA-DR*0402 to tumor-infiltrating T cells in cervical cancer. [2019]