Engineered NK Cell Therapy for Multiple Myeloma

Recruiting in Palo Alto (17 mi)

Overseen by Muzaffar Qazilbash, MD

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1 & 2

Recruiting

Sponsor: M.D. Anderson Cancer Center

Must not be taking: Corticosteroids, Live vaccines

Disqualifiers: Autoimmune diseases, Active infection, others

No Placebo Group

Approved in 1 Jurisdiction

Trial Summary

What is the purpose of this trial?

To find the recommended dose of NY-ESO-1 TCR/IL-15 NK cells that can be given to patients with relapsed or refractory MM. To learn if the dose of NY-ESO-1 TCR/IL-15 NK cells found in Part A can help to control the disease.

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop taking your current medications, but you must be at least two weeks from your last anti-myeloma therapy before starting the trial's chemotherapy. You may continue certain targeted therapies until three days before starting chemotherapy.

What data supports the effectiveness of the treatment Engineered NK Cell Therapy for Multiple Myeloma?

Research shows that engineered NK cells, like those used in this treatment, can effectively kill multiple myeloma cells and improve patient outcomes. Studies have demonstrated that NK cells expanded with specific methods can enhance their ability to target and destroy cancer cells, suggesting potential benefits for multiple myeloma patients. ^{1 2 3 4 5}

Is engineered NK cell therapy for multiple myeloma safe for humans?

Research shows that engineered NK cell therapies, including those using NY-ESO-1 TCR-engineered T cells, are generally well tolerated in humans, with no significant safety concerns like cytokine-release syndrome observed in trials. These therapies have been tested in multiple myeloma patients and have shown promising safety profiles. ^{1 2 5 6 7}

What makes the NY-ESO-1 TCR/IL-15 NK cell treatment unique for multiple myeloma?

The NY-ESO-1 TCR/IL-15 NK cell treatment is unique because it combines engineered natural killer (NK) cells with a T-cell receptor (TCR) targeting NY-ESO-1, a cancer-testis antigen, and interleukin-15 (IL-15) to enhance the NK cells' persistence and function. This approach is novel as it leverages both TCR targeting and cytokine support to potentially improve outcomes in multiple myeloma, where standard NK cell therapies have been less effective. ^{1 2 3 5 7}

Research Team

Muzaffar Qazilbash, MD

Principal Investigator

M.D. Anderson Cancer Center

Eligibility Criteria

This trial is for adults aged 18-80 with relapsed/refractory multiple myeloma, who haven't had recent vaccines or systemic steroids, and have no active infections. Participants must weigh at least 40 kg, not be on live vaccines or certain therapies targeting NY-ESO-1, and practice birth control. They should also have adequate organ function and a specific immune system marker (HLA-A*02:01).

Inclusion Criteria

Signed consent to long-term follow-up protocol PA17-0483 to fulfill the institutional responsibilities to various regulatory agencies

I finished my last myeloma treatment at least 2 weeks ago.

I do not have any ongoing or untreated infections.

Exclusion Criteria

Not applicable.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment Part A

Participants receive NY-ESO-1 TCR/IL-15 NK cells to assess dose-limiting toxicity and determine the optimal cell dose

12 weeks

Treatment Part B

Participants treated at the optimal cell dose to assess the day +90 overall response rate

12 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment, including day +180 progression-free survival and immune reconstitution studies

24 weeks

Treatment Details

Interventions

• Cyclophosphamide (Alkylating agents)
• Fludarabine phosphate (Anti-metabolites)
• NY-ESO-1 TCR/IL-15 NK cells (CAR T-cell Therapy)

Trial Overview The study tests genetically engineered NK cells with NY-ESO-1 TCR/IL-15 receptors alongside drugs Cyclophosphamide and Fludarabine phosphate to find the best dose for controlling multiple myeloma that has come back or resisted treatment.

Participant Groups

Group I: Part B: Cell therapy with NY-ESO-1 TCR/IL-15 NK - INPATIENT Experimental Treatment 3 Interventions

Group II: Part B2: Cell therapy with NY-ESO-1 TCR/IL-15 NK - OUTPATIENT Experimental Treatment 3 Interventions

Group III: Part A: Cell therapy with NY-ESO-1 TCR/IL-15 NK - INPATIENT Experimental Treatment 3 Interventions

Group IV: Part A2: Cell therapy with NY-ESO-1 TCR/IL-15 NK - OUTPATIENT Experimental Treatment 3 Interventions

Who Is Running the Clinical Trial?

M.D. Anderson Cancer Center

Lead Sponsor

Trials

3,107

Recruited

1,813,000+

Dr. Peter WT Pisters

M.D. Anderson Cancer Center

Chief Executive Officer since 2017

MD from University of Western Ontario

Dr. Jeffrey E. Lee

M.D. Anderson Cancer Center

Chief Medical Officer

MD from Stanford University School of Medicine

Findings from Research

The study developed four different CAR-NK cell products targeting BCMA, with the BCMA-CD28-IL15 CAR-NK cells showing the strongest ability to kill tumor cells and secrete cytokines, indicating their potential effectiveness in treating multiple myeloma.

In a mouse model, the BCMA-CD28-IL15 CAR-NK cells not only inhibited tumor growth but also improved survival rates, suggesting a promising avenue for immunotherapy with a lower risk of cytokine release syndrome compared to traditional CAR-T cell therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Single VHH-directed BCMA CAR-NK cells for multiple myeloma. Ren, Q., Zu, Y., Su, H., et al.[2023]

A new method using genetically engineered K562 cells expressing OX40 ligand and membrane-bound IL-18 and IL-21 significantly enhances the expansion of natural killer (NK) cells from multiple myeloma patients, achieving a 4,929-fold increase over 28 days.

The expanded NK cells not only showed increased activation markers but also demonstrated enhanced ability to kill multiple myeloma cells, indicating a promising approach for improving NK cell-based immunotherapy in treating this cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Expansion of cytotoxic natural killer cells in multiple myeloma patients using K562 cells expressing OX40 ligand and membrane-bound IL-18 and IL-21. Thangaraj, JL., Phan, MT., Kweon, S., et al.[2022]

In a phase I/II trial involving 20 patients with multiple myeloma, autologous T cells engineered to target the NY-ESO-1 and LAGE-1 antigens were found to be safe and well-tolerated, with no significant cytokine-release syndrome despite high IL-6 levels.

The treatment showed promising efficacy, with 80% of patients experiencing clinical responses and a median progression-free survival of 19.1 months, indicating that the engineered T cells effectively targeted and attacked the cancer cells.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

NY-ESO-1-specific TCR-engineered T cells mediate sustained antigen-specific antitumor effects in myeloma. Rapoport, AP., Stadtmauer, EA., Binder-Scholl, GK., et al.[2022]

Quadruple gene-engineered NK cells derived from induced pluripotent stem cells (iPSCs) show promising results in targeting multiple myeloma, demonstrating durable antitumor activity in preclinical models without needing additional cytokines.

These engineered NK cells are designed for mass production and include features like a chimeric antigen receptor targeting BCMA and a CD16 modification to enhance their effectiveness when combined with anti-CD38 antibodies, making them a potential off-the-shelf treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Quadruple gene-engineered natural killer cells enable multi-antigen targeting for durable antitumor activity against multiple myeloma. Cichocki, F., Bjordahl, R., Goodridge, JP., et al.[2023]

References

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

Engineering Anti-myeloma Responses Using Affinity-Enhanced TCR-Engineered T Cells. [2015]

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

Single VHH-directed BCMA CAR-NK cells for multiple myeloma. [2023]

3. Italy pubmed.ncbi.nlm.nih.gov

Highly activated and expanded natural killer cells for multiple myeloma immunotherapy. [2021]

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

Improving NK cell function in multiple myeloma with NKTR-255, a novel polymer-conjugated human IL-15. [2023]

5. Germany pubmed.ncbi.nlm.nih.gov

Expansion of cytotoxic natural killer cells in multiple myeloma patients using K562 cells expressing OX40 ligand and membrane-bound IL-18 and IL-21. [2022]

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

NY-ESO-1-specific TCR-engineered T cells mediate sustained antigen-specific antitumor effects in myeloma. [2022]

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

Quadruple gene-engineered natural killer cells enable multi-antigen targeting for durable antitumor activity against multiple myeloma. [2023]