E7 TCR T Cell Therapy for HPV-Related Cancers

Overseen By Laura A Parsons-Wandell, R.N.

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: National Cancer Institute (NCI)

Must not be taking: Immunosuppressants, Corticosteroids

Disqualifiers: Active infections, Autoimmune diseases, others

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

Approved in 1 Jurisdiction This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 2

Duration: Up to 12 days

180 Participants Needed

Trial Summary

What is the purpose of this trial?

Background: Human papillomavirus (HPV) can cause cervical, throat, anal, and genital cancers. Cancers caused by HPV have a HPV protein called E7 inside of their cells. In this new therapy, researchers take a person s blood, remove certain white blood cells, and insert genes that make them to target cancer cells that have the E7 protein. The genetically changed cells, called E7 TCR cells, are then given back to the person to fight the cancer. Researchers want to see if this can help people. Objective: To determine a safe dose and efficacy of E7 TCR cells and whether these cells can help patients. Eligibility: Adults ages 18 and older with an HPV-16-associated cancer, including cervical, vulvar, vaginal, penile, anal, or oropharyngeal. Design: Participants will list all their medicines. Participants will have many screening tests, including imaging procedures, heart and lung tests, and lab tests. They will have a large catheter inserted into a vein. Participants will have leukapheresis. Blood will be removed through a needle in the arm. A machine separates the white blood cells. The rest of the blood is returned through a needle in the other arm. The cells will be changed in the lab. Participants will stay in the hospital. Over several days, they will get: Chemotherapy drugs E7 TCR cells Shots or injections to stimulate the cells Participants will be monitored in the hospital up to 12 days. They will get support medicine and have blood and lab tests. Participants will have a clinic visit about 40 days after cell infusion. They will have a physical exam, blood work, scans, and maybe x-rays. Participants will have many follow-up visits with the same procedures. At some visits, they may undergo leukapheresis. Participants will be followed for 15 years.

Will I have to stop taking my current medications?

The trial does not specify if you must stop taking your current medications, but it mentions that more than four weeks must have passed since any prior systemic therapy before receiving the E7 TCR cells. It's best to discuss your current medications with the trial team.

What data supports the effectiveness of the E7 TCR T Cell Therapy treatment for HPV-related cancers?

Research shows that E7 TCR T Cell Therapy can effectively target and kill HPV-16+ cancer cells in lab settings and animal models, leading to tumor regression. This suggests potential for treating HPV-related cancers in humans. ^{1 2 3 4 5}

Is E7 TCR T Cell Therapy for HPV-related cancers safe for humans?

Research suggests that T cell therapies targeting HPV proteins like E7 appear to be safe, as they specifically target cancer cells without affecting healthy tissues. However, detailed human safety data is limited, and more studies are needed to confirm safety in clinical settings. ^{1 2 3 4 6}

How is E7 TCR T Cell Therapy different from other treatments for HPV-related cancers?

E7 TCR T Cell Therapy is unique because it involves genetically engineering T cells to specifically target and kill cancer cells expressing the HPV-16 E7 protein, which is not found in healthy tissues. This approach allows for precise targeting of cancer cells, potentially leading to more effective treatment with fewer side effects compared to traditional therapies. ^{1 2 3 4 5}

Research Team

Scott M Norberg, D.O.

Principal Investigator

National Cancer Institute (NCI)

Eligibility Criteria

Adults 18+ with HPV-16-associated cancers (cervical, vulvar, vaginal, penile, anal, oropharyngeal) who've tried standard treatments or declined them. Must have proper liver and kidney function, acceptable blood counts, no more than three treated brain metastases. HIV negative and not on immunosuppressants except for certain exceptions.

Inclusion Criteria

My cancer is HPV-16 positive and can be measured.

I have either received or declined the first round of standard treatment.

I am fully active or can carry out light work.

Exclusion Criteria

I do not have active infections, bleeding disorders, or severe heart, lung, or immune system diseases.

Any other condition, which would, in the opinion of the Principal Investigator, indicate that the subject is a poor candidate for the clinical trial or would jeopardize the subject or the integrity of the data obtained

I am on immunosuppressive drugs, but not for minor local uses or as a reaction premedication.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Multiple visits for imaging, heart and lung tests, and lab tests

Leukapheresis and Cell Engineering

Blood is removed, white blood cells are separated and genetically modified in the lab

1 week

1 visit for leukapheresis

Treatment

Participants receive chemotherapy drugs, E7 TCR cells, and injections to stimulate the cells

Up to 12 days

Inpatient stay for treatment administration

Initial Follow-up

Participants have a clinic visit about 40 days after cell infusion for physical exam, blood work, and scans

1 week

1 clinic visit

Long-term Follow-up

Participants are monitored for safety and effectiveness, with follow-up visits every 3 months for the first year, then every 6 months for up to 5 years, and as per PI discretion thereafter

15 years

Regular follow-up visits

Treatment Details

Interventions

• E7 TCR cells

Trial Overview The trial tests E7 TCR cells therapy where patients' white blood cells are genetically modified to target cancer cells containing the HPV protein E7. It includes chemotherapy drugs Cyclophosphamide and Fludarabine followed by an infusion of these modified cells plus Aldesleukin shots to stimulate them.

Participant Groups

Group I: Arm 2: Phase II Experimental Treatment 4 Interventions

1 x 10 e11 E7 Cells that was determined in Phase I + aldesleukin

Group II: Arm 1: Phase I Experimental Treatment 4 Interventions

Non-myeloablative, lymphocyte depleting preparative regimen, followed by E7 TCR Cells at escalating doses, followed by aldesleukin

E7 TCR cells is already approved in United States for the following indications:

Approved in United States as E7 TCR cells for:

• Human Papillomavirus-Associated Cancers
• Cervical cancer
• Oropharyngeal cancer
• Anal cancer
• Genital cancers

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

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]

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]

The study successfully isolated T cell receptor (TCR) genes from HPV16E7-specific T cell clones, demonstrating the feasibility of genetically engineering CD8+ T cells to express these TCRs for potential use in adoptive immunotherapy against cervical cancer.

Transgenic T cells showed effective recognition and response to HPV16E7-specific antigens, indicating that this approach could be a promising strategy for generating targeted T cell therapies for patients with cervical cancer and other HPV16-related cancers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Preservation and redirection of HPV16E7-specific T cell receptors for immunotherapy of cervical cancer. Scholten, KB., Schreurs, MW., Ruizendaal, JJ., et al.[2010]

T cells engineered to target the HPV-16 E6 oncoprotein were able to specifically recognize and kill HPV-positive tumor cells, demonstrating their potential as an effective immunotherapy for HPV-associated cancers.

In a patient with metastatic anal cancer, the engineered T cells showed a significantly higher frequency of a specific T-cell clonotype in the tumor compared to peripheral blood, indicating a strong anti-tumor response that could be harnessed for treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Targeting of HPV-16+ Epithelial Cancer Cells by TCR Gene Engineered T Cells Directed against E6. Draper, LM., Kwong, ML., Gros, A., et al.[2019]

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]

In a study involving 68 patients with HPV-associated cancers, researchers successfully reactivated and expanded T cells that specifically target HPV E6 and E7 proteins, achieving over a 1200-fold increase in T cell numbers from a significant portion of cervical and oropharyngeal cancer patients.

The presence of specific cytokines (IL-6, IL-7, IL-12, and IL-15) was crucial for the reactivation process, and the resulting T-cell lines showed promising characteristics for potential use in adoptive immunotherapy, indicating a scalable and compliant method for treating HPV16-related cancers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Human papillomavirus type 16 E6/E7-specific cytotoxic T lymphocytes for adoptive immunotherapy of HPV-associated malignancies. Ramos, CA., Narala, N., Vyas, GM., et al.[2021]

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

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

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

Preservation and redirection of HPV16E7-specific T cell receptors for immunotherapy of cervical cancer. [2010]

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

Targeting of HPV-16+ Epithelial Cancer Cells by TCR Gene Engineered T Cells Directed against E6. [2019]

5. England pubmed.ncbi.nlm.nih.gov

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

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

Human papillomavirus type 16 E6/E7-specific cytotoxic T lymphocytes for adoptive immunotherapy of HPV-associated malignancies. [2021]