E7 TCR T Cell Therapy for HPV-Related Cancers

Recruiting in Palo Alto (17 mi)

Overseen by Scott M Norberg, D.O.

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1 & 2

Recruiting

Sponsor: National Cancer Institute (NCI)

Must not be taking: Immunosuppressants, Corticosteroids

Disqualifiers: Active infections, Autoimmune diseases, others

No Placebo Group

Approved in 1 Jurisdiction

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.

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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.

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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.

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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.

Trial 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

Participant Groups

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.

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

Find a Clinic Near You

Research Locations Nearby Select from list below to view details:

National Institutes of Health Clinical Center Bethesda, MD

Who Is Running the Clinical Trial?

National Cancer Institute (NCI) Lead Sponsor

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] T cell receptor (TCR) T cell therapy is a promising cancer treatment modality. However, its successful development for epithelial cancers may depend on the identification of high-avidity TCRs directed against tumor-restricted target antigens. The human papillomavirus (HPV) E7 antigen is an attractive therapeutic target that is constitutively expressed by HPV+ cancers but not by healthy tissues. It is unknown if genetically engineered TCR T cells that target E7 can mediate regression of HPV+ cancers. We identified an HPV-16 E7-specific, HLA-A*02:01-restricted TCR from a uterine cervix biopsy from a woman with cervical intraepithelial neoplasia. This TCR demonstrated high functional avidity, with CD8 coreceptor-independent tumor targeting. Human T cells transduced to express the TCR specifically recognized and killed HPV-16+ cervical and oropharyngeal cancer cell lines and mediated regression of established HPV-16+ human cervical cancer tumors in a mouse model. These findings support the therapeutic potential of this approach and established the basis for an E7 TCR gene therapy clinical trial in patients with metastatic HPV+ cancers (NCT02858310).

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] High-risk human papillomavirus (HPV) infection is a causal factor in oropharyngeal and gynecological malignancies, and development of HPV-targeted immunotherapy could be used to treat patients with these cancers. T cell-mediated adoptive immunotherapy targeting E6 and E7, two HPV16 proteins consistently expressed in tumor cells, appears to be both attractive and safe. However, isolation of HPV-specific T cells is difficult owing to the low frequency of these cell precursors in the peripheral blood. In addition, HPV-positive cancer cells often down-regulate major histocompatibility complex (MHC) class I expression ex vivo, limiting the efficacy of MHC class I-restricted approaches. Of particular interest is that both CD4 and CD8 T cells can mediate the responses. Given that CD4 T cells play a critical role in coordinating effective antitumor responses, the generation of a T helper response in patients with HPV16-associated malignancies would unleash the ultimate potential of immunotherapy. In this view, T-cell receptor (TCR) gene transfer could be a relevant strategy to generate HPV16-E7-specific and MHC class II-restricted T cells in sufficient numbers. An HPV16-E7/HLA-DRB1*04 TCR has been isolated from a cancer patient with complete response, and retroviral particles encoding this TCR have been produced. The transgenic TCR is highly expressed in transduced T cells, with a functional inducible caspase-9 suicide gene safety cassette. TCR transgenic T cells are HPV16-E770-89 specific and HLA-DRB1*04 restricted, as determined by interferon (IFN)-γ secretion. CD8 and CD4 T cells are equivalently transduced and secrete interleukin-2 and IFN-γ when cultured with appropriate targets. We also demonstrate that TCR transgenic T cells recognize the endogenously processed and presented HPV16-E770-89 peptide. In conclusion, our data indicate that the production of MHC class II-restricted HPV16-E7-specific T cells is feasible through TCR gene transfer and could be used for immunotherapy.

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

Preservation and redirection of HPV16E7-specific T cell receptors for immunotherapy of cervical cancer. [2010] Human papilloma virus (HPV) type 16 infections of the genital tract are associated with the development of cervical cancer (CxCa) in women. HPV16-derived oncoproteins E6 and E7 are expressed constitutively in these lesions and might therefore be attractive candidates for T-cell-mediated adoptive immunotherapy. However, the low precursor frequency of HPV16E7-specific T cells in patients and healthy donors hampers routine isolation of these cells for adoptive transfer. To overcome this problem, we have isolated T cell receptor (TCR) genes from four different HPV16E7-specific healthy donor and patient-derived human cytotoxic T lymphocyte (CTL) clones. We examined whether genetic engineering of peripheral blood-derived CD8+ T cells in order to express HPV16E711-20-specific TCRs is feasible for adoptive transfer purposes. Reporter cells (Jurkat/MA) carrying a transgenic TCR were shown to bind relevant but not irrelevant tetramers. Moreover, these TCR-transgenic Jurkat/MA cells showed reactivity towards relevant target cells, indicating proper functional activity of the TCRs isolated from already available T cell clones. We next introduced an HPV16E711-20-specific TCR into blood-derived, CD8+ recipient T cells. Transgenic CTL clones stained positive for tetramers presenting the relevant HPV16E711-20 epitope and biological activity of the TCR in transduced CTL was confirmed by lytic activity and by interferon (IFN)-gamma secretion upon antigen-specific stimulation. Importantly, we show recognition of the endogenously processed and HLA-A2 presented HPV16E711-20 CTL epitope by A9-TCR-transgenic T cells. Collectively, our data indicate that HPV16E7 TCR gene transfer is feasible as an alternative strategy to generate human HPV16E7-specific T cells for the treatment of patients suffering from cervical cancer and other HPV16-induced malignancies.

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] The E6 and E7 oncoproteins of HPV-associated epithelial cancers are in principle ideal immunotherapeutic targets, but evidence that T cells specific for these antigens can recognize and kill HPV(+) tumor cells is limited. We sought to determine whether TCR gene engineered T cells directed against an HPV oncoprotein can successfully target HPV(+) tumor cells.

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] Infection with high risk Human Papilloma Virus (HPV) is associated with cancer of the cervix, vagina, penis, vulva, anus and some cases of head and neck carcinomas. The HPV derived oncoproteins E6 and E7 are constitutively expressed in tumor cells and therefore potential targets for T cell mediated adoptive immunotherapy. Effective immunotherapy is dependent on the presence of both CD4+ and CD8+ T cells. However, low precursor frequencies of HPV16 specific T cells in patients and healthy donors hampers routine isolation of these cells for adoptive transfer purposes. An alternative to generate HPV specific CD4+ and CD8+ T cells is TCR gene transfer.

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] Vaccines prevent human papillomavirus (HPV)-associated cancer but, although these tumors express foreign, viral antigens (E6 and E7 proteins), they have little benefit in established malignancies, likely due to negative environmental cues that block tumor recognition and induce T-cell anergy in vivo. We postulated that we could identify mechanisms by which ex vivo stimulation of T cells could reactivate and expand tumor-directed T-cell lines from HPV cancer patients for subsequent adoptive immunotherapy. A total of 68 patients with HPV-associated cancers were studied. Peripheral blood T cells were stimulated with monocyte-derived dendritic cells loaded with pepmixes [peptide libraries of 15-mers overlapping by 11 amino acids (aa)] spanning E6/E7, in the presence or absence of specific accessory cytokines. The resulting T-cell lines were further expanded with pepmix-loaded activated B-cell blasts. Interferon-γ release and cytotoxic responses to E6/E7 were assessed. We successfully reactivated and expanded (>1200-fold) E6-specific/E7-specific T cells from 8/16 cervical and 33/52 oropharyngeal cancer patients. The presence of the cytokines interleukin (IL)-6, IL-7, IL-12, and IL-15 is critical for this process. These T-cell lines possess the desirable characteristics of polyclonality, multiple T-cell subset representation (including the memory compartment) and a TH1 bias, and may eliminate E6/E7 targets. In conclusion, we have shown it is possible to robustly generate HPV16 E6/E7-directed T-cell lines from patients with HPV16-associated cancers. Because our technique is scalable and good-manufacturing procedures-compliant, these lines could be used for adoptive cellular immunotherapy of patients with HPV16 cancers.