HPV-Specific T Cell Therapy for Recurrent/Metastatic Cancer

Overseen By Tanguy Seiwert, M.D.

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Must be taking: Anti-PD-1, Anti-PD-L1

Must not be taking: Immunosuppressants, Steroids

Disqualifiers: Immunodeficiency, Autoimmune disease, Active infection, others

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

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 6 weeks

24 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new HPV-specific T cell therapy for individuals with hard-to-treat HPV16-related cancers that have recurred or metastasized. Researchers aim to evaluate the treatment's effectiveness by comparing two methods: a bone marrow transplant and a special lymphocyte infusion. Suitable candidates for this trial have incurable HPV16+ head and neck cancer that has recurred or spread, have previously undergone certain treatments, and have a partially matched family donor. As a Phase 1/Phase 2 trial, it provides the opportunity to be among the first to receive this new treatment and to help assess its effectiveness in a smaller group.

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, you should discuss your current medications with the trial team to ensure they don't interfere with the study.

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

Research has shown that the allogeneic HPV-specific T cell treatment appears safe. Patients have responded well, with improved survival rates. Studies have found an increase in CD8+ T cells, a type of immune cell, indicating a strong immune response. Some side effects have been observed, but they are usually manageable. As this treatment remains in the early stages of testing, researchers closely monitor safety and side effects. While early results are positive, more research is needed to fully understand long-term safety. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments because they use allogeneic HPV-specific T cells to target recurrent or metastatic cancers linked to the human papillomavirus (HPV), offering a new approach distinct from traditional therapies like chemotherapy and radiation. Unlike these existing treatments, which can be nonspecific and affect healthy cells, the allogeneic T cell therapy aims to harness the body's immune system to specifically attack cancer cells. This precision could potentially result in fewer side effects and improve effectiveness. Additionally, the use of a non-myeloablative bone marrow transplant and CD8-depleted donor lymphocyte infusion could enhance the immune response, providing a robust and targeted attack against the cancer.

What evidence suggests that this trial's treatments could be effective for recurrent/metastatic HPV-associated cancer?

Research has shown that using special immune cells from a relative can help fight cancers linked to HPV 16. In this trial, participants may receive either an allogeneic bone marrow transplant or a CD8-depleted donor lymphocyte infusion from a haploidentical relative after vaccination with a therapeutic HPV vaccine series. These cells are trained to find and attack cancer cells. Studies have found that this method can lead to promising results, including improved survival rates for patients with HPV-related cancers. The treatment helps the immune system recognize and destroy cancer cells caused by HPV. Although this research remains in the early stages, it suggests potential benefits for patients with recurring or spreading HPV 16-related cancers. ^{1 3 6 7 8}

Who Is on the Research Team?

Tanguy Seiwert, M.D.

Principal Investigator

Johns Hopkins Sidney Kimmel Comprehensive Cancer Center

Are You a Good Fit for This Trial?

Adults with recurrent or metastatic HPV16+ cancers who've had platinum-based treatment, an ECOG status <2, and a haploidentical related donor. They must have tried anti-PD-1/PD-L1 therapy if indicated, measurable disease per RECIST 1.1, and adequate organ function. Exclusions include those with curable local disease options, recent immunosuppressive treatments, active autoimmune diseases or infections, pregnancy/breastfeeding without contraception use.

Inclusion Criteria

aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 4 x institutional upper limit of normal

I have had at least one cycle of PD-1 or PD-L1 therapy.

I have been treated with a platinum-based chemotherapy before.

Exclusion Criteria

Inability to comply with study procedures

Pregnancy or breastfeeding: females of childbearing potential must have a negative serum pregnancy test.

I have had pneumonitis treated with steroids or have it now.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Vaccination

Haploidentical relatives are vaccinated with a therapeutic HPV vaccine series to generate HPV-specific leukocytes

4 weeks

Treatment

Patients are randomized to either non-myeloablative allogeneic bone marrow transplant or CD8-depleted donor lymphocyte infusion

6 weeks

Follow-up

Participants are monitored for safety, effectiveness, and incidence of acute GVHD, with assessments at 2, 6, and 12 months

12 months

What Are the Treatments Tested in This Trial?

Interventions

• Allogeneic HPV-specific T Cells

Trial Overview The trial is testing the safety and effectiveness of two approaches using immune cells from vaccinated relatives: either a non-myeloablative bone marrow transplant or an infusion of CD8-depleted T cells to treat adults with HPV16+ cancers that have come back or spread.

How Is the Trial Designed?

Group I: CD8-depleted donor lymphocyte infusion (DLI) per dose escalation scheme Experimental Treatment 1 Intervention

CD8-depleted donor lymphocyte infusion per dose escalation scheme from a haploidentical relative after vaccination with a therapeutic HPV vaccine series.

Group II: Allogeneic bone marrow transplant Experimental Treatment 1 Intervention

non-myeloablative allogeneic bone marrow transplant (BMT) from a haploidentical relative after vaccination with a therapeutic HPV vaccine series.

Allogeneic HPV-specific T Cells is already approved in United States, European Union for the following indications:

Approved in United States as HPV-specific T-cell therapy for:

• Recurrent or metastatic HPV16+ cancers

Approved in European Union as Allogeneic virus-specific T cells for:

• HPV-associated malignancies

Who Is Running the Clinical Trial?

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Lead Sponsor

Trials

578

Recruited

33,600+

PapiVax Biotech, Inc.

Collaborator

Trials

6

Recruited

120+

Published Research Related to This Trial

The study developed HLA-A24&-E dual integrated HPV-specific cytotoxic T lymphocytes (HPV-rejTs) that can evade immune rejection while effectively suppressing cervical cancer, offering a potential 'off-the-shelf' treatment option.

Single-cell RNA sequencing revealed that these HPV-rejTs are enriched with tissue resident memory T cells, enhancing their cytotoxicity through TGFβR signaling and improved T cell receptor activation, which may lead to more effective cancer cell targeting.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

iPSC-derived hypoimmunogenic tissue resident memory T cells mediate robust anti-tumor activity against cervical cancer. Furukawa, Y., Ishii, M., Ando, J., et al.[2023]

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]

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]

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]

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]

A new manufacturing platform has been developed to create HPV-specific T cells from healthy donors, achieving a significant 578-fold expansion of these cells, which could be used to treat patients with high-risk HPV-associated cancers.

By optimizing the conditions for T cell production, including enhancing dendritic cell function and using specific cytokines, researchers have improved the efficacy of these T cells, making them a promising option for patients who do not respond to existing therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Human papilloma virus-specific T cells can be generated from naïve T cells for use as an immunotherapeutic strategy for immunocompromised patients. McCormack, SE., Cruz, CRY., Wright, KE., et al.[2020]

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]

Cervical cancer, primarily caused by HPV16, is linked to a weak immune response, particularly a lack of strong T-helper type 1 (Th1) immunity against HPV16 oncoproteins, which suggests that enhancing this immune response is crucial for effective treatment.

A successful protocol was developed to enrich HPV16E6-specific CD4(+) T cells from healthy donors, which could be pivotal for future adoptive T cell therapies in advanced cervical cancer, as these cells can help activate tumor-fighting mechanisms.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rapid enrichment of human papillomavirus (HPV)-specific polyclonal T cell populations for adoptive immunotherapy of cervical cancer. de Jong, A., van der Hulst, JM., Kenter, GG., et al.[2018]

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]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT04713046

NCT04713046 | Safety and Efficacy of Allogeneic HPV ... In this study, haploidentical relatives of a patient with recurrent or metastatic HPV 16-associated malignancy will be vaccinated with a therapeutic human ...

2. centerwatch.com centerwatch.com/clinical-trials/listings/NCT04713046/safety-and-efficacy-of-allogeneic-hpv-specific-t-cells-in-adults-with-recurrent-or-metastatic-hpv16-cancers

Safety and Efficacy of Allogeneic HPV-specific T Cells in ... In this study, haploidentical relatives of a patient with recurrent or metastatic HPV 16-associated malignancy will be vaccinated with a ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12115775/

Update: Immunotherapeutic Strategies in HPV-Associated ... We will review the current standard of checkpoint inhibitor immunotherapy in the recurrent or metastatic setting, focusing on outcomes in HPV- ...

4. jamanetwork.com jamanetwork.com/journals/jamaoncology/fullarticle/2830546

Novel Combination Immunotherapy and Clinical Activity in ... This trial identified a population of patients with HPV-associated cancer with promising antitumor responses and improved survival.

5. sciencedirect.com sciencedirect.com/science/article/pii/S2950194625003619

HPV-Specific Antivirals: Disarming Viral Entry and ... This study examined various aspects of advanced antiviral therapy. In the field of capsid protein inhibitors, compounds that directly target ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11843463/

Novel Combination Immunotherapy and Clinical Activity in ... This trial identified a population of patients with HPV-associated cancer with promising antitumor responses and improved survival, supporting ...

7. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/36455147/

Safety and Efficacy of MEDI0457 plus Durvalumab in ... HPV-16/18-specific T cells increased on treatment; 4 of 8 evaluable patients had a >2-fold increase in tumor-infiltrating CD8+ T cells.

8. clinicaltrials.gov clinicaltrials.gov/study/NCT02858310

Study Details | NCT02858310 | E7 TCR T Cells for Human ... 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 ...