Engineered T Cells for Blood Cancer

(RESOLVE Trial)

Recruiting in Palo Alto (17 mi)

+1 other location

Age: Any Age

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1

Recruiting

Sponsor: Catherine Bollard

Must not be taking: PD-1 inhibitors

Disqualifiers: Uncontrolled infections, Active GVHD, others

No Placebo Group

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

Trial 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

Participant Groups

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.

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)

Find a Clinic Near You

Research Locations Nearby Select from list below to view details:

Childrens National Medical Center Washington, United States

Kenneth R. Cooke, MD Baltimore, MD

Who Is Running the Clinical Trial?

Catherine Bollard Lead Sponsor

Children's National Research Institute Collaborator

Johns Hopkins University Collaborator

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] Tumor-associated antigen cytotoxic T cells (TAA-Ts) represent a new, potentially effective and nontoxic therapeutic approach for patients with relapsed or refractory solid tumors. In this first-in-human trial, we investigated the safety of administering TAA-Ts that target Wilms tumor gene 1, preferentially expressed antigen of melanoma, and survivin to patients with relapsed/refractory solid tumors.

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

T-Cell Receptor-Based Immunotherapy for Hematologic Malignancies. [2023] Adoptive immunotherapy with engineered T cells is at the forefront of cancer treatment. T cells can be engineered to express T-cell receptors (TCRs) specific for tumor-associated antigens (TAAs) derived from intracellular or cell surface proteins. T cells engineered with TCRs (TCR-T) allow for targeting diverse types of TAAs, including proteins overexpressed in malignant cells, those with lineage-restricted expression, cancer-testis antigens, and neoantigens created from abnormal, malignancy-restricted proteins. Minor histocompatibility antigens can also serve as TAAs for TCR-T to treat relapsed hematologic malignancies after allogeneic hematopoietic cell transplantation. Moreover, TCR constructs can be modified to improve safety and enhance function and persistence of TCR-T. Transgenic T-cell receptor therapies targeting 3 different TAAs are in early-phase clinical trials for treatment of hematologic malignancies. Preclinical studies of TCR-T specific for many other TAAs are underway and offer great promise as safe and effective therapies for a wide range of cancers.

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

Production of multiple CTL epitopes from multiple tumor-associated antigens. [2014] Identification of antigenic peptides derived from tumor-associated antigens (TAA) enables cancer vaccine therapy using antigenic peptides. Here, we summarize the design of antigenic peptides and induction of cytotoxic T lymphocytes (CTL) using antigenic peptides and validation of CTL.

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] To investigate the safety and efficacy of tumor-associated antigen-specific cytotoxic T lympho- cytes (TAA-CTL) in the treatment of multiple myeloma (MM) and non-Hodgkin lymphoma (NHL).

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] Relapse is a major problem in acute myeloid leukemia (AML) and adversely affects survival. Tumor-associated antigen-specific cytotoxic T lymphocyte (TAA-CTLs)-based therapy was introduced and increasingly used clinically to kill tumor cells via tumor antigen activation.

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

Improving the efficacy and safety of engineered T cell therapy for cancer. [2020] Adoptive T-cell therapy (ACT) using tumor-infiltrating lymphocytes (TILs) is a powerful immunotherapeutics approach against metastatic melanoma. The success of TIL therapy has led to novel strategies for redirecting normal T cells to recognize tumor-associated antigens (TAAs) by genetically engineering tumor antigen-specific T cell receptors (TCRs) or chimeric antigen receptor (CAR) genes. In this manner, large numbers of antigen-specific T cells can be rapidly generated compared with the longer term expansion of TILs. Great efforts have been made to improve these approaches. Initial clinical studies have demonstrated that genetically engineered T cells can mediate tumor regression in vivo. In this review, we discuss the development of TCR and CAR gene-engineered T cells and the safety concerns surrounding the use of these T cells in patients. We highlight the importance of judicious selection of TAAs for modified T cell therapy and propose solutions for potential "on-target, off-organ" toxicity.

7. Switzerland pubmed.ncbi.nlm.nih.gov

T-Cell Immunotherapies Targeting Histocompatibility and Tumor Antigens in Hematological Malignancies. [2021] Over the last decades, T-cell immunotherapy has revealed itself as a powerful, and often curative, strategy to treat blood cancers. In hematopoietic cell transplantation, most of the so-called graft-vs.-leukemia (GVL) effect hinges on the recognition of histocompatibility antigens that reflect immunologically relevant genetic variants between donors and recipients. Whether other variants acquired during the neoplastic transformation, or the aberrant expression of gene products can yield antigenic targets of similar relevance as the minor histocompatibility antigens is actively being pursued. Modern genomics and proteomics have enabled the high throughput identification of candidate antigens for immunotherapy in both autologous and allogeneic settings. As such, these major histocompatibility complex-associated tumor-specific (TSA) and tumor-associated antigens (TAA) can allow for the targeting of multiple blood neoplasms, which is a limitation for other immunotherapeutic approaches, such as chimeric antigen receptor (CAR)-modified T cells. We review the current strategies taken to translate these discoveries into T-cell therapies and propose how these could be introduced in clinical practice. Specifically, we discuss the criteria that are used to select the antigens with the greatest therapeutic value and we review the various T-cell manufacturing approaches in place to either expand antigen-specific T cells from the native repertoire or genetically engineer T cells with minor histocompatibility antigen or TSA/TAA-specific recombinant T-cell receptors. Finally, we elaborate on the current and future incorporation of these therapeutic T-cell products into the treatment of hematological malignancies.

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

Trick to treat: tricking the thymus to treat cancer. [2021] In this issue of Blood, Schmitt et al address the biology and safety of T cells engineered to express T-cell receptor (TCR) variants endowed with enhanced affinity for tumor-associated antigens.