TAA-Specific CTL Therapy for Lymphoma

(TACTAL Trial)

Recruiting at 1 trial location

Overseen By George Carrum, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Baylor College of Medicine

Must be taking: Azacytidine

Must not be taking: Systemic corticosteroids

Disqualifiers: Severe infection, HIV, Hepatitis, others

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

Compensation: Varies

Number of Visits: 10

36 Participants Needed

Trial Summary

What is the purpose of this trial?

Patients have a type of lymph gland disease called Hodgkin or non-Hodgkin lymphoma which has come back, or may come back, or has not gone away after treatment, including the standard treatment known for these diseases. This a research study using special immune system cells called tumor associated antigen (TAA)-specific cytotoxic T lymphocytes, a new experimental therapy. This sort of therapy has been used previously to treat Hodgkin or non-Hodgkin lymphomas that show proof of infection with Epstein-Barr virus (EBV), the virus that causes infectious mononucleosis ("mono" or the "kissing disease"). EBV is found in cancer cells of up to half of all patients with Hodgkin's and non-Hodgkin lymphoma. This suggests that it may play a role in causing lymphoma. The cancer cells infected by EBV are able to hide from the body's immune system and escape being killed. Investigators tested whether special white blood cells, called T cells, that were trained to kill EBV-infected cells could affect these tumors, and in many patients it was found that giving these trained T cells caused a complete or partial response. However, many patients do not have EBV in their lymphoma cells; therefore investigators now want to test whether it is possible to direct these special T cells against other types of proteins on the tumor cell surface with similar promising results. The proteins that will be targeted in this study are called tumor associated antigens (TAAs) - these are cell proteins that are specific to the cancer cell, so they either do not show or show up in low quantities on normal human cells. In this study, we will target five TAAs which commonly show on lymphoma, called: NY-ESO-1, MAGEA4, PRAME, Survivin and SSX. This will be done by using special types of T cells called cytotoxic T lymphocytes (CTLs) generated in the lab. In addition, some adult patients will receive a drug called azacytidine before giving the T cells. We hope that the combination helps the T cells work better.

Will I have to stop taking my current medications?

The trial requires that participants stop taking conventional therapy, including rituximab, at least one week before joining the study. Additionally, participants should not be on other investigational therapies for one month prior to the study.

What data supports the effectiveness of the TAA-Specific CTL Therapy for Lymphoma treatment?

Research shows that TAA-specific T cells, when used alone or with other treatments like nivolumab, are safe and can help control disease progression in patients with relapsed or refractory Hodgkin lymphoma. Additionally, similar T-cell therapies have shown promise in treating other types of cancer, suggesting potential effectiveness for lymphoma. ^{1 2 3 4 5}

Is TAA-Specific CTL Therapy for Lymphoma safe for humans?

Research shows that TAA-specific T cells, when used alone or with another drug called nivolumab, were safe in patients with relapsed or refractory Hodgkin lymphoma, with no major side effects reported. This suggests that the therapy is generally safe for humans. ^{1 2 3 5 6}

How is the TAA-Specific CTL Therapy for Lymphoma different from other treatments?

This treatment is unique because it uses T cells (a type of immune cell) that are specifically trained to target multiple tumor-associated antigens (TAAs) found in lymphoma, potentially making it more effective for certain patients. It combines this approach with azacytidine, a drug that may enhance the immune response, and involves a dose-escalation stage to find the optimal dose, which is not common in standard lymphoma treatments. ^{1 3 7 8 9}

Research Team

Geoge Carrum, MD

Principal Investigator

Baylor College of Medicine

Eligibility Criteria

This trial is for adults and children with Hodgkin or non-Hodgkin lymphoma that has returned after treatment, hasn't responded to treatment, or as a second cancer. Participants need a certain level of hemoglobin, normal organ function tests, and must not be pregnant. They should not have severe infections, HIV, hepatitis B/C infection or be on systemic steroids.

Inclusion Criteria

I have been diagnosed with Hodgkin or non-Hodgkin lymphoma.

PROCUREMENT: Life expectancy of 6 weeks or greater

PROCUREMENT: Patient and/or parent/guardian able to give informed consent

Exclusion Criteria

PROCUREMENT: Patients with active HIV infection at time of procurement (can be pending at the time of blood draw)

I am currently taking corticosteroids.

I am allergic to azacitidine or mannitol.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Antigen-Escalation

Patients receive TAA-specific T cells targeting increasing numbers of TAAs to evaluate safety

8 weeks

2 infusions, 28 days apart

Dose-Escalation

Patients receive increasing doses of T cells to evaluate safety

6 weeks

2 infusions, 14 days apart

Aza Stage

Adult patients receive azacytidine followed by T cell infusions to test combination therapy

3 months

3 cycles of aza, 2 T cell infusions

Pediatric Stage

Pediatric patients receive T cell infusions to test safety and efficacy

2 weeks

2 infusions, 14 days apart

Follow-up

Participants are monitored for safety and effectiveness after treatment

1 year

Regular blood tests and imaging studies

Long-term Follow-up

Annual follow-up to evaluate disease response long-term

4 years

Treatment Details

Interventions

• Antigen-Escalation Stage
• azacytidine and multiTAA T cells Stage
• Dose-Escalation Stage
• Pediatric multiTAA T cells Stage

Trial Overview The study is testing TAA-specific cytotoxic T lymphocytes (CTLs), which are immune cells designed to target proteins commonly found on lymphoma cells. Some adult patients will also receive azacytidine before the CTLs to potentially enhance the effectiveness of the therapy.

Participant Groups

Group I: azacytidine and multiTAA T cells Stage Experimental Treatment 1 Intervention

This phase will administer aza intravenously at a dose of 75 mg/m2 after premedication with an anti-emetic such as ondansetron po or IV (up to a maximum dose of 16 mg ondansetron or equivalent). This phase will determine whether infusion of TAA-specific T cells (at dose level 2 - 1x10\^7) targeting multiple tumor antigens in combination with azacytidine is safe, and whether CTL infusions (with or without azacytidine) increase the spectrum of epitopes/antigens targeted by endogenous T cells (epitope spreading).

Group II: Pediatric multiTAA T cells Stage Experimental Treatment 1 Intervention

This phase will give patients \< 18 years old two infusions (on Day 0 and Day 14) of multi-TAA specific T cells at a fixed dose of 1x10\^7 cells/m2. This phase will test the safety and efficacy of multiTAA-specific T cells in pediatric patients with active HL/NHL.

Group III: Dose-Escalation Study Stage Experimental Treatment 1 Intervention

In the dose escalation stage, three dose levels will be studied. Patients in the dose escalation portion of the study will be entered and stratified separately to the following two groups: Group A: Patients receiving CTLs as therapy for Hodgkin's or non-Hodgkin's lymphoma. Group B: Patients receiving CTLs as adjunctive therapy following autologous or syngeneic transplant.

Group IV: Antigen-Escalation Stage Experimental Treatment 1 Intervention

The first stage will be an "antigen-escalation" stage using a fixed total dose of cells (5 x 10\^6 cells/m\^2 x 2) to evaluate the safety of the T cells primed against PRAME pepmix, and then SSX pepmix, and then MAGE A4 pepmix, and then NY-ESO pepmix, and then SURVIVIN pepmix.

Who Is Running the Clinical Trial?

Baylor College of Medicine

Lead Sponsor

Trials

1,044

Recruited

6,031,000+

Center for Cell and Gene Therapy, Baylor College of Medicine

Collaborator

Trials

114

Recruited

2,900+

The Methodist Hospital Research Institute

Collaborator

Trials

299

Recruited

82,500+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Findings from Research

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 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]

Chimeric antigen receptor (CAR) T-cell therapies have shown promising results in treating patients with relapsed or refractory B-cell non-Hodgkin lymphoma, offering complete and lasting clinical responses where traditional therapies have failed.

Four CD19-directed CAR T-cell therapies have been approved by the FDA for specific types of relapsed or refractory lymphomas, indicating a significant advancement in treatment options for these challenging cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Relapsed/Refractory Non-Hodgkin Lymphoma: Engineering T-Cells to Express Chimeric Antigen Receptors (CARs), a Salvage? Kanwal, B.[2021]

A new method has been developed to generate cytotoxic T lymphocytes (CTLs) that can target a variety of nonviral tumor-associated antigens in Hodgkin and non-Hodgkin lymphoma, potentially expanding treatment options for EBV-negative tumors.

This approach successfully produced CTLs from all nine healthy donors and five out of eight lymphoma patients, demonstrating its effectiveness across different human leukocyte antigen (HLA) types and suggesting a promising avenue for immunotherapy in a broader range of lymphoma cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cytotoxic T lymphocytes simultaneously targeting multiple tumor-associated antigens to treat EBV negative lymphoma. Gerdemann, U., Katari, U., Christin, AS., et al.[2021]

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]

References

1. 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]

2. England pubmed.ncbi.nlm.nih.gov

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

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

Tumor-associated antigen-specific T cells with nivolumab are safe and persist in vivo in relapsed/refractory Hodgkin lymphoma. [2022]

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

Management of patients with non-Hodgkin's lymphoma: focus on adoptive T-cell therapy. [2020]

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

Relapsed/Refractory Non-Hodgkin Lymphoma: Engineering T-Cells to Express Chimeric Antigen Receptors (CARs), a Salvage? [2021]

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

5-azacytidine promotes an inhibitory T-cell phenotype and impairs immune mediated antileukemic activity. [2021]

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

Cytotoxic T lymphocytes simultaneously targeting multiple tumor-associated antigens to treat EBV negative lymphoma. [2021]

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

Active antigen-specific immunotherapy of melanoma: from basic science to clinical investigation. [2023]

9. 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]