Engineered T Cells for Blood Cancer

(RESOLVE Trial)

Recruiting at 1 trial location

Overseen By Fahmida Hoq, MBBS, MS

Age: Any Age

Sex: Any

Trial Phase: Phase 1

Sponsor: Catherine Bollard

Must not be taking: PD-1 inhibitors

Disqualifiers: Uncontrolled infections, Active GVHD, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: 5 months

90 Participants Needed

Trial Summary

What is the purpose of this trial?

This Phase I dose-escalation trial is designed to evaluate the safety of administering rapidly -generated tumor multi-antigen associated -specific cytotoxic T lymphocytes, to HSCT recipients (Arm A) or future HSCT recipients (Arm B) for the treatment of high-risk or relapsed or refractory hematopoietic malignancies. In addition to safety, this study will also evaluate if event-free survival (EFS) is improved with TAA-T administration at six months after HSCT for patients with high risk AML and MDS (Arm C).

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, certain medications like PD-1 inhibitors or other T cell activating agents are excluded for some participants, and investigational therapies are not allowed within 28 days prior to the infusion.

What data supports the effectiveness of the treatment Tumor-associated antigen-specific T lymphocytes (TAA-T) for blood cancer?

Research shows that TAA-T cells have been used effectively in treating relapsed or refractory solid tumors and hematologic malignancies (blood cancers). These engineered T cells target specific proteins found in cancer cells, helping to kill them and potentially preventing relapse in conditions like acute myeloid leukemia. ^{1 2 3 4 5}

Is engineered T cell therapy safe for humans?

Research shows that engineered T cells targeting tumor-associated antigens have been used safely in early clinical trials for various cancers, including solid tumors and blood cancers. These studies suggest that the treatment is generally safe, with efforts made to minimize potential side effects. ^{1 2 4 5 6}

How is the treatment Tumor associated antigen lymphocytes (TAA-T) different from other treatments for blood cancer?

Tumor associated antigen lymphocytes (TAA-T) are unique because they are engineered T cells specifically designed to target multiple tumor-associated antigens (TAAs) found in blood cancers, allowing for a more precise attack on cancer cells. This approach differs from other treatments like chimeric antigen receptor (CAR) T cells, which typically target a single antigen, potentially making TAA-Ts more versatile and effective against a broader range of cancer cells. ^{1 2 4 7 8}

Eligibility Criteria

This trial is for people aged 6 months to 80 years with certain high-risk blood cancers or tumors who have had, or will have, a stem cell transplant. They must be in relatively good health otherwise and agree to use contraception if applicable. Pregnant women, those with severe graft-versus-host disease (GVHD), uncontrolled infections, or recent treatment with certain immune therapies are excluded.

Inclusion Criteria

I am between 6 months and 80 years old.

Agree to use contraceptive measures during study protocol participation

I (or my guardian) can understand and agree to the study's terms.

Exclusion Criteria

I do not have any infections that are not responding to treatment.

Pregnancy or lactating (female of childbearing potential)

No investigational therapies within 28 days prior to TAA-T infusion

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive tumor multi-antigen associated specific cytotoxic T lymphocytes (TAA-T) with dose escalation to evaluate safety and efficacy

5 months

Multiple infusions based on dose level and response

Follow-up

Participants are monitored for safety, including acute GVHD and other adverse events, and effectiveness after TAA-T infusion

1 year

Long-term follow-up

Event-free and overall survival are assessed, and incidence and severity of GVHD are monitored

2 years

Treatment Details

Interventions

• Tumor associated antigen lymphocytes (TAA-T)

Trial Overview The study tests TAA-T cells in patients receiving stem cell transplants for aggressive blood cancers. It's divided into three arms: A) post-transplant patients; B) pre-transplant patients; C) post-transplant without relapse. The goal is to see if these cells improve survival without the cancer returning after six months.

Participant Groups

Group I: Tumor associated antigen lymphocytes (TAA-T) Experimental Treatment 1 Intervention

For Arm A Patients (post-HSCT): TAA-T will be infused any time after neutrophil engraftment post-HSCT or day 30, whichever comes first. For Arm B Patients (pre-HSCT): TAA-T will be infused any time \> 7 days after previous therapy for relapsed disease. For Arm C Patients (post-HSCT): TAA-T will be infused any time after neutrophil engraftment post-HSCT or day 30, whichever comes first. All infusions will be within 5 months post-HSCT. Five different dosing levels will be evaluated. Two to four patients will be evaluated on each dosing schedule (see below). This protocol is designed as a phase I dose-escalation study. Dose Level One: 5 x 106 cells/m2 Dose Level Two: 1 x 107 cells/m2 Dose Level Three: 2 x 107 cells/m2 Dose Level Four: 4 x 107 cells/m2 Dose Level Five: 1 x 108 cells/m2 (ONLY applicable to Arm A patients) Arm C patients will ONLY be enrolled at: Dose Level Four (4 x 107 cells/m2)

Who Is Running the Clinical Trial?

Catherine Bollard

Lead Sponsor

Trials

13

Recruited

290+

Children's National Research Institute

Collaborator

Trials

227

Recruited

258,000+

Johns Hopkins University

Collaborator

Trials

2,366

Recruited

15,160,000+

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]

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]

The study focuses on creating antigenic peptides from tumor-associated antigens (TAA) to develop effective cancer vaccines.

These antigenic peptides are designed to stimulate cytotoxic T lymphocytes (CTL), which are crucial for targeting and destroying cancer cells, and the effectiveness of this CTL induction is validated in the research.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Production of multiple CTL epitopes from multiple tumor-associated antigens. Morita, R., Hirohashi, Y., Nakatsugawa, M., et al.[2014]

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]

In a study involving 9 patients with acute myeloid leukemia (AML) at high risk of relapse, the infusion of tumor-associated antigen-specific cytotoxic T lymphocytes (TAA-CTLs) showed promising safety, with no significant adverse reactions reported during or after treatment.

The TAA-CTL therapy demonstrated an antileukemic effect in 2 out of 5 patients who were minimal residual disease (MRD) positive, indicating potential efficacy in reducing leukemia without the need for additional chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

T cells targeting multiple tumor-associated antigens as a postremission treatment to prevent or delay relapse in acute myeloid leukemia. Xue, L., Hu, Y., Wang, J., et al.[2022]

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]

The study by Schmitt et al. explores the biology and safety of T cells that have been genetically modified to express T-cell receptor (TCR) variants, which have a stronger ability to recognize tumor-associated antigens.

These engineered T cells show promise for improving cancer immunotherapy by potentially enhancing the effectiveness of the immune response against tumors while maintaining safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Trick to treat: tricking the thymus to treat cancer. Bonini, C., Mondino, A.[2021]

T-cell immunotherapy has emerged as a powerful treatment for blood cancers, leveraging the graft-vs.-leukemia (GVL) effect, which relies on recognizing histocompatibility antigens between donors and recipients.

Modern genomics and proteomics are enabling the identification of tumor-specific and tumor-associated antigens, which can enhance the effectiveness of T-cell therapies by targeting multiple blood neoplasms, thus overcoming limitations seen in other immunotherapeutic strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

T-Cell Immunotherapies Targeting Histocompatibility and Tumor Antigens in Hematological Malignancies. Janelle, V., Rulleau, C., Del Testa, S., et al.[2021]

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

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

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

Production of multiple CTL epitopes from multiple tumor-associated antigens. [2014]

4. 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]

5. New Zealand pubmed.ncbi.nlm.nih.gov

T cells targeting multiple tumor-associated antigens as a postremission treatment to prevent or delay relapse in acute myeloid leukemia. [2022]

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

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

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

Trick to treat: tricking the thymus to treat cancer. [2021]

8. Switzerland pubmed.ncbi.nlm.nih.gov

T-Cell Immunotherapies Targeting Histocompatibility and Tumor Antigens in Hematological Malignancies. [2021]