TAA-T Cell Therapy for Solid Cancers

Overseen By Fahmida Hoq, MBBS

Age: Any Age

Sex: Any

Trial Phase: Phase 1

Sponsor: Children's National Research Institute

Must not be taking: Immunosuppressants, Chemotherapy

Disqualifiers: HIV, Pregnancy, Allogeneic transplant, others

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

Compensation: Varies

Number of Visits: 2

Duration: 45 days

36 Participants Needed

Trial Summary

What is the purpose of this trial?

This is a phase I dose-escalation study to evaluate the safety of partially human leukocyte antigen (HLA)-matched multi tumor-associated antigen-specific T cell (TAA-T) therapy for patients with high-risk solid tumors due to the presence of refractory, relapsed and/or minimal residual detectable disease following conventional therapy. Conventional therapy may include chemotherapy, surgery, radiation, autologous stem cell transplant, or targeted therapy.

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 must not have taken systemic steroids within 1 week of the TAA-T infusion and certain immunosuppressive medications within 28 days. If you are receiving lymphodepleting chemotherapy, you should not have taken chemotherapy or immunomodulatory medications within the last 2 weeks before treatment.

What data supports the effectiveness of the TAA-T Cell Therapy treatment for solid cancers?

Research shows that TAA-T cells, which are a type of immune cell therapy, have been used safely in patients with difficult-to-treat solid tumors. Additionally, similar therapies have shown promise in causing lasting tumor regression in certain cancers, suggesting potential effectiveness. ^{1 2 3 4 5}

Is TAA-T cell therapy safe for humans?

TAA-T cell therapy has been studied in early trials for various cancers, including solid tumors and breast cancer, and is considered potentially nontoxic. However, there are safety concerns about potential 'on-target, off-organ' toxicity, where the therapy might mistakenly attack normal tissues that share antigens with the tumor. ^{1 6 7 8 9}

How is TAA-T Cell Therapy different from other treatments for solid cancers?

TAA-T Cell Therapy is unique because it uses specially modified T cells that are trained to recognize and attack specific proteins found on cancer cells, making it a targeted and potentially less toxic treatment option compared to traditional therapies. ^{1 4 9 10 11}

Eligibility Criteria

This trial is for patients with high-risk solid tumors like Ewing sarcoma or neuroblastoma, who have not responded well to standard treatments. Participants must be in stable condition without recent steroid use or infections and agree to contraception if applicable. They should match at least one HLA allele with the TAA-T therapy and meet specific health criteria such as adequate organ function.

Inclusion Criteria

My blood tests show enough neutrophils and platelets while on chemotherapy.

My liver enzymes are within a normal range for my age.

Pulse oximetry of >90% on room air

Exclusion Criteria

I haven't received specific immune system treatments in the last 28 days.

Pregnant or lactating females

I had a stem cell transplant using my own cells within the last 60 days.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive TAA-T therapy with dose escalation to determine safety and anti-tumor activity

45 days

1 visit (in-person) for each infusion

Follow-up

Participants are monitored for safety and effectiveness after TAA-T infusion

45 days

1 visit (in-person) at day 45

Extension

Additional dose of TAA-T may be administered if criteria are met

Minimum of 45 days apart from the first dose

Treatment Details

Interventions

• Tumor-associated antigen-specific T cell (TAA-T)

Trial Overview The study tests a new cancer treatment using T cells that target tumor-associated antigens (TAA-T). It's for those whose tumors express certain antigens and haven't improved after conventional therapies. The trial will gradually increase doses to find the safest amount of TAA-T cells that can be given.

Participant Groups

Group I: Arm B for patients age ≥6 years and <18 years Experimental Treatment 1 Intervention

Arm B will enroll patients age ≥6 years and \<18 years. TAA-T product will first be administered to patients as monotherapy at dose level 1 to determine safety. Following demonstration of safety in dose level 1, lymphodepleting chemotherapy will be administered prior to the first dose of TAA-Ts on the dose escalation phase (dose levels 2 and 3). The TAA-T product will be assessed for safety and anti-tumor activity.

Group II: Arm A for patients age ≥18 years and <70 years Experimental Treatment 1 Intervention

Arm A will enroll patients age ≥18 years and \<70 years. TAA-T product will first be administered to patients as monotherapy at dose level 1 to determine safety. Following demonstration of safety in dose level 1, lymphodepleting chemotherapy will be administered prior to the first dose of TAA-Ts on the dose escalation phase (dose levels 2 and 3). The TAA-T product will be assessed for safety and anti-tumor activity.

Who Is Running the Clinical Trial?

Children's National Research Institute

Lead Sponsor

Trials

227

Recruited

258,000+

Findings from Research

In a first-in-human trial involving 15 patients with relapsed or refractory solid tumors, tumor-associated antigen cytotoxic T cells (TAA-Ts) were administered safely without any dose-limiting toxicities, demonstrating a promising new therapeutic approach.

Of the evaluable patients, 73% showed stable disease or better at day 45 post-infusion, with 6 patients remaining progression-free for a median of 13.9 months, indicating that TAA-Ts can effectively stabilize disease and prolong time to progression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immunotherapy of Relapsed and Refractory Solid Tumors With Ex Vivo Expanded Multi-Tumor Associated Antigen Specific Cytotoxic T Lymphocytes: A Phase I Study. Hont, AB., Cruz, CR., Ulrey, R., et al.[2020]

Naturally occurring T cells that target tumor-associated antigens (TAAs) are frequently found in cancer patients, indicating that tumors may have some level of immunogenicity.

The review highlights that while certain TAAs elicit strong T cell responses, others do not, suggesting that understanding these differences is key to developing effective T cell-directed immunotherapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Natural T cell immunity against cancer. Nagorsen, D., Scheibenbogen, C., Marincola, FM., et al.[2022]

There is growing interest in therapeutic vaccination as a cancer treatment, moving beyond early vaccines that used whole tumor cells or fragments, which had limited success.

Current research is focused on developing next-generation cancer vaccines that target specific tumor-associated antigens (TAAs), with ongoing efforts to identify and deliver these antigens effectively for better therapeutic outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tumor-associated antigens: from discovery to immunity. Lewis, JD., Reilly, BD., Bright, RK.[2022]

Human T cells can be genetically modified to express tumor-associated antigens, making them potential candidates for effective antigen-presenting cells in cancer immunotherapy.

The successful induction of tumor-specific T cell immune responses requires the activation of T cells using CD3/CD28 antibodies along with proinflammatory cytokines like IL-7 and IL-12, highlighting the importance of these components in developing cellular cancer vaccines.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Modification of T lymphocytes to express tumor antigens. Foster, AE., Song, XT.[2021]

Adoptive T-cell therapy (ACT) has shown the ability to induce complete and lasting tumor regression in certain cancers, particularly metastatic melanoma, with some patients potentially being cured.

Recent advancements in identifying mutated gene products as targets for TILs and the use of engineered T cells (like those expressing chimeric antigen receptors) suggest that ACT could be expanded to treat a wider range of malignancies beyond melanoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Exploiting the curative potential of adoptive T-cell therapy for cancer. Hinrichs, CS., Rosenberg, SA.[2023]

Adoptive T-cell therapy using tumor-infiltrating lymphocytes (TILs) has shown significant promise in treating metastatic melanoma, leading to the development of genetically engineered T cells that can specifically target tumor-associated antigens (TAAs).

Initial clinical studies indicate that these genetically engineered T cells, including those with tumor antigen-specific T cell receptors (TCRs) and chimeric antigen receptors (CARs), can effectively cause tumor regression, although safety concerns, particularly regarding potential 'on-target, off-organ' toxicity, must be carefully managed.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Improving the efficacy and safety of engineered T cell therapy for cancer. Shi, H., Liu, L., Wang, Z.[2020]

In a first-in-human trial involving 10 heavily pre-treated patients with relapsed or metastatic breast cancer, multi-antigen-targeted T cells (multiTAA-T) were well tolerated with no treatment-related toxicities, indicating a promising safety profile for this therapy.

One patient experienced prolonged disease stabilization for 5 months, which was linked to the in vivo expansion and persistence of T cells targeting specific tumor antigens, along with evidence of broader immune activation against non-targeted tumor antigens in 7 out of 10 patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Multi-antigen-targeted T-cell therapy to treat patients with relapsed/refractory breast cancer. Hoyos, V., Vasileiou, S., Kuvalekar, M., et al.[2022]

Adoptive cellular therapy, particularly using tumor-infiltrating lymphocytes (TILs), shows significant promise in treating cancers like melanoma, indicating a need for further development in clinical settings.

Genetically engineered T cells can enhance antitumor activity, but there are risks of toxicity when these cells target normal tissues, highlighting the need for careful balance in future therapies and clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Development of adoptive cell therapy for cancer: a clinical perspective. Hawkins, RE., Gilham, DE., Debets, R., et al.[2021]

Tumor-associated antigen-specific cytotoxic T lymphocytes (TAA-CTL) were safely generated and infused into patients with multiple myeloma and non-Hodgkin lymphoma, with no significant adverse reactions reported during the treatment.

In a small group of 7 patients, TAA-CTL therapy showed promising efficacy, as 5 patients experienced positive clinical effects, and an increase in specific immune responses was observed 2-3 weeks post-infusion.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Clinical Research of Dendritic Cell-Mediated Tumor-Associated Antigen-Specific Cytotoxic T Lymphocytes in the Treatment of Multiple Myeloma and Non-Hodgkin Lymphoma]. Li, XH., Xue, L., Xu, H., et al.[2020]

Engineered T cells expressing T-cell receptors (TCRs) can specifically target tumor-associated antigens (TAAs), making them a promising approach in cancer treatment, particularly for hematologic malignancies.

Current early-phase clinical trials are testing TCR-T therapies targeting three different TAAs, while preclinical studies are exploring many more, indicating a broad potential for safe and effective cancer therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

T-Cell Receptor-Based Immunotherapy for Hematologic Malignancies. Biernacki, MA., Brault, M., Bleakley, M.[2023]

Recombinant monoclonal antibodies (MAbs) are becoming important in cancer therapy, especially when used alongside traditional anti-cancer drugs, enhancing treatment effectiveness.

Combining antibody therapy with toxins or radioisotopes, and developing immune cells like cytotoxic T-lymphocytes (CTLs) or natural killer (NK) cells that target tumor-associated antigens (TAAs), could significantly improve cancer immunotherapy outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Possible applications of antibodies or their genes in cancer therapy. Kuroki, M., Huang, J., Shibaguchi, H., et al.[2007]

References

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

Immunotherapy of Relapsed and Refractory Solid Tumors With Ex Vivo Expanded Multi-Tumor Associated Antigen Specific Cytotoxic T Lymphocytes: A Phase I Study. [2020]

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

Natural T cell immunity against cancer. [2022]

3. England pubmed.ncbi.nlm.nih.gov

Tumor-associated antigens: from discovery to immunity. [2022]

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

Modification of T lymphocytes to express tumor antigens. [2021]

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

Exploiting the curative potential of adoptive T-cell therapy for cancer. [2023]

6. Ireland pubmed.ncbi.nlm.nih.gov

Improving the efficacy and safety of engineered T cell therapy for cancer. [2020]

7. England pubmed.ncbi.nlm.nih.gov

Multi-antigen-targeted T-cell therapy to treat patients with relapsed/refractory breast cancer. [2022]

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

Development of adoptive cell therapy for cancer: a clinical perspective. [2021]

9. China pubmed.ncbi.nlm.nih.gov

[Clinical Research of Dendritic Cell-Mediated Tumor-Associated Antigen-Specific Cytotoxic T Lymphocytes in the Treatment of Multiple Myeloma and Non-Hodgkin Lymphoma]. [2020]

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

T-Cell Receptor-Based Immunotherapy for Hematologic Malignancies. [2023]

11. Greece pubmed.ncbi.nlm.nih.gov

Possible applications of antibodies or their genes in cancer therapy. [2007]