TAA-Specific Cytotoxic T-Lymphocytes for Multiple Myeloma

(TACTAM Trial)

Recruiting in Palo Alto (17 mi)

+2 other locations

Overseen by Premal Lulla, MD

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1

Recruiting

Sponsor: Baylor College of Medicine

Must be taking: Lenalidomide, Thalidomide, Pomalidomide, Checkpoint inhibitors

Must not be taking: Systemic corticosteroids

Disqualifiers: Severe infection, Active HIV, Pregnant, others

No Placebo Group

Trial Summary

What is the purpose of this trial?

This study is for patients that have a cancer called Multiple Myeloma, monoclonal gammopathy of undetermined significance (MGUS) or smoldering myeloma (SM). MGUS and SM have tumor cells that possess nearly identical properties to the cancer cells seen in patients with multiple myeloma. The investigators would like to target proteins that are expressed by these cells using the patient's own immune cells known as T lymphocytes.This research study uses special immune system cells called tumor associated antigen (TAA)-specific cytotoxic T lymphocytes (CTLs), a new experimental therapy. The proteins that investigators are targeting in this study are called tumor associated antigens (TAAs). These are cell proteins that are specific to the cancer cell.They either do not show or show up in low quantities on normal human cells. In this study the investigators are targeting five common TAAs called NY-ESO-1, MAGEA4, PRAME, Survivin and SSX. On a different protocol, patients have been treated and so far this treatment has shown to be safe. Investigators now want to try this treatment in patients with multiple myeloma or if the investigators can arrest the progression of the patient's condition condition (described above) to multiple myeloma. These TAA-specific CTLs are an investigational product not approved by the Food and Drug Administration. The purpose of this study is to find the largest safe dose of TAA-specific CTLs, to learn what the side effects are, and to see whether this therapy might help patients with multiple myeloma monoclonal gammopathy of undetermined significance (MGUS) or smoldering myeloma (SM) .

Do I need to stop my current medications for the trial?

You need to stop any investigational therapy for one month and conventional therapy for at least 48 hours before joining the study, except for certain medications like lenalidomide, thalidomide, pomalidomide, or immune checkpoint inhibitors.

What data supports the effectiveness of the TAA-specific CTLs treatment for multiple myeloma?

Research shows that TAA-specific cytotoxic T-lymphocytes (special immune cells) can be generated to target specific proteins found in multiple myeloma cells, suggesting they might help fight this cancer. Similar approaches have been used to treat other types of cancer, like non-Hodgkin lymphoma, by targeting tumor-associated antigens. ^{1 2 3 4 5}

Is TAA-specific CTL therapy safe for humans?

Research shows that TAA-specific cytotoxic T-lymphocytes (T-cells that target cancer cells) have been tested in humans and are considered a potentially safe treatment option for various cancers, including multiple myeloma and solid tumors. ^{1 2 4 6 7}

How is the TAA-specific CTL treatment different from other treatments for multiple myeloma?

TAA-specific CTL treatment is unique because it uses the body's own immune cells, specifically cytotoxic T-lymphocytes, to target and destroy cancer cells by recognizing specific tumor-associated antigens (proteins found on cancer cells). This approach is different from traditional treatments as it aims to provide a more targeted and potentially less toxic option for patients with multiple myeloma. ^{1 2 5 8 9}

Research Team

Premal Lulla, MD

Principal Investigator

Baylor College of Medicine/Houston Methodist Hospital

Eligibility Criteria

This trial is for adults over 18 with Multiple Myeloma, high-risk MGUS, or smoldering myeloma. Participants must have had at least one prior treatment if they have Multiple Myeloma and should expect to live more than six weeks. They need a certain level of blood oxygen, liver function, and kidney function to join. Pregnant women can't participate; others must use effective birth control.

Inclusion Criteria

Patients should have been off other investigational therapy for one month prior to entry in this study

I am 18 or older with high risk MGUS or smoldering myeloma.

I am 18 or older with high risk MGUS/smoldering myeloma or have multiple myeloma and received treatment.

Exclusion Criteria

You have an ongoing HIV infection at the time of blood collection.

I am currently suffering from a severe infection.

I have taken corticosteroids within 2 days before receiving a CTL infusion.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants receive TAA-specific CTLs with initial two doses given two weeks apart, followed by up to six additional doses at monthly intervals if disease is stable or decreased

8-32 weeks

8 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment, with blood tests and imaging studies conducted at specified intervals

1 year

Regular visits (in-person) and annual contact for up to 5 years

Long-term follow-up

Participants are contacted annually to evaluate disease response long-term

4 additional years

Treatment Details

Interventions

• TAA-specific CTLs (CAR T-cell Therapy)

Trial Overview The study tests TAA-specific CTLs (immune cells) against five cancer cell proteins in patients with multiple myeloma or related conditions. The goal is to find the highest safe dose of these cells, understand side effects, and see if this therapy helps prevent disease progression.

Participant Groups

Group I: Group C Experimental Treatment 1 Intervention

Patients with high risk MGUS or smoldering myeloma receiving a fixed dose TAA-Specific CTLs

Group II: Group B Experimental Treatment 1 Intervention

Patients receiving TAA-Specific CTLs as adjunctive therapy following autologous or syngeneic transplant for myeloma

Group III: Group A Experimental Treatment 1 Intervention

Patients receiving TAA-specific CTLs as therapy for Myeloma

Who Is Running the Clinical Trial?

Baylor College of Medicine

Lead Sponsor

Trials

1,044

Recruited

6,031,000+

Paul Klotman

Baylor College of Medicine

Chief Executive Officer since 2010

MD, PhD

James Versalovic

Baylor College of Medicine

Chief Medical Officer since 2020

MD from Baylor College of Medicine

Harris County Hospital District

Collaborator

Trials

7

Recruited

410+

The Methodist Hospital Research Institute

Collaborator

Trials

299

Recruited

82,500+

Dr. John P. Cooke

The Methodist Hospital Research Institute

Chief Medical Officer since 2013

MD, PhD

Dr. Jenny Chang

The Methodist Hospital Research Institute

Chief Executive Officer

MBBChir from University of Cambridge, MHCM from Johns Hopkins University

Center for Cell and Gene Therapy, Baylor College of Medicine

Collaborator

Trials

114

Recruited

2,900+

Dr. Helen E. Heslop

Center for Cell and Gene Therapy, Baylor College of Medicine

Chief Executive Officer since 2017

M.D. from University of Otago, New Zealand

Dr. Chrystal U. Louis

Center for Cell and Gene Therapy, Baylor College of Medicine

Chief Medical Officer since 2024

M.D. from Tulane University School of Medicine

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]

Hybrid cell lines created from EBV B-lymphoblastoid cells and myeloma cells successfully stimulated the production of antigen-specific, cytotoxic T-lymphocytes in peripheral blood lymphocytes from multiple myeloma patients, indicating a potential new approach for immunotherapy.

This study highlights that these hybrid cell lines can effectively target tumor-associated antigens (TAAs) like hTERT, MUC1, MAGE-C1, and CS1, which are commonly expressed in multiple myeloma, suggesting they could enhance the effectiveness of adoptive immunotherapy for this challenging cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

In vitro Generation of Cytotoxic T Cells With Potential for Adoptive Tumor Immunotherapy of Multiple Myeloma. Khalaf, WS., Garg, M., Mohamed, YS., et al.[2020]

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]

Cytotoxic T lymphocytes (CTLs) play a crucial role in fighting cancer by recognizing tumor-specific antigens, which are presented by cells in the body.

The review discusses the development of peptide-based vaccines that target these tumor-associated antigens, highlighting their potential to enhance the immune response against cancer and improve CTL therapy in the future.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Tumor antigen-specific cytotoxic T lymphocytes and cancer immunotherapy - review]. Liu, Y.[2016]

This study successfully identified and expanded myeloma-specific precursor cytotoxic T cells (pCTL) from a patient with multiple myeloma in complete remission, demonstrating a novel approach to targeting cancer cells.

The isolated CD8+ cytotoxic T-cell clone (CT5) showed specific recognition and cytotoxicity against the patient's myeloma cells while sparing other healthy cells, indicating a potential for targeted immunotherapy in multiple myeloma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Isolation of human lymphocyte antigens class I-restricted cytotoxic T lymphocytes against autologous myeloma cells. Pellat-Deceunynck, C., Jego, G., Harousseau, JL., et al.[2006]

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]

In a study involving 12 chronic lymphocytic leukemia (CLL) patients, MDM2-specific T cells were successfully generated in 7 patients, demonstrating the potential of MDM2 as a tumor-associated antigen for immunotherapy.

The study found that the ability of antigen-presenting cells (APCs) to secrete IFN-gamma was a key factor in generating effective MDM2-specific T cells, highlighting the importance of APC functionality in developing targeted immune responses against tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

MDM2 is recognized as a tumor-associated antigen in chronic lymphocytic leukemia by CD8+ autologous T lymphocytes. Mayr, C., Bund, D., Schlee, M., et al.[2020]

An autologous T cell therapy targeting multiple tumor-associated antigens (mTAAs) was tested in 21 patients with high-risk, relapsed or refractory multiple myeloma, showing good tolerance with only two cases of transient grade III adverse events.

Patients receiving this therapy experienced longer than expected progression-free survival, with some achieving objective responses, indicating that this approach may provide a promising long-term benefit for difficult-to-treat multiple myeloma cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The safety and clinical effects of administering a multiantigen-targeted T cell therapy to patients with multiple myeloma. Lulla, PD., Tzannou, I., Vasileiou, S., et al.[2021]

Myeloma cells are more susceptible to destruction by WT1-specific cytotoxic T lymphocytes (CTLs) compared to lymphoma cells, despite similar levels of WT1 expression, indicating a unique sensitivity in myeloma cells.

The study suggests that the effectiveness of CTL-mediated cytotoxicity is influenced by the extent of membrane damage caused by perforin, making WT1 a promising target for immunotherapy in multiple myeloma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Myeloma cells are highly sensitive to the granule exocytosis pathway mediated by WT1-specific cytotoxic T lymphocytes. Azuma, T., Otsuki, T., Kuzushima, K., et al.[2013]

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. Switzerland pubmed.ncbi.nlm.nih.gov

In vitro Generation of Cytotoxic T Cells With Potential for Adoptive Tumor Immunotherapy of Multiple Myeloma. [2020]

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

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

4. China pubmed.ncbi.nlm.nih.gov

[Tumor antigen-specific cytotoxic T lymphocytes and cancer immunotherapy - review]. [2016]

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

Isolation of human lymphocyte antigens class I-restricted cytotoxic T lymphocytes against autologous myeloma cells. [2006]

6. 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]

7. Netherlands pubmed.ncbi.nlm.nih.gov

MDM2 is recognized as a tumor-associated antigen in chronic lymphocytic leukemia by CD8+ autologous T lymphocytes. [2020]

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

The safety and clinical effects of administering a multiantigen-targeted T cell therapy to patients with multiple myeloma. [2021]

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

Myeloma cells are highly sensitive to the granule exocytosis pathway mediated by WT1-specific cytotoxic T lymphocytes. [2013]