Engineered NK Cell Therapy for Multiple Myeloma

Overseen By Muzaffar Qazilbash, M D

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: M.D. Anderson Cancer Center

Must not be taking: Corticosteroids, Live vaccines

Disqualifiers: Autoimmune diseases, Active infection, others

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

Approved in 1 Jurisdiction This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

44 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new type of cell therapy for treating multiple myeloma, a form of blood cancer. The research aims to determine the safest dose of engineered NK cells (NY-ESO-1 TCR/IL-15 NK cells) for patients whose disease has returned or is unresponsive to other treatments. It targets individuals with long-standing multiple myeloma who have unsuccessfully tried several treatments. Participants must have specific characteristics in their tumor samples and have undergone at least four different treatments. As a Phase 1, Phase 2 trial, this research seeks to understand the treatment's effects and measure its initial effectiveness, offering participants a chance to contribute to groundbreaking advancements in multiple myeloma therapy.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that NY-ESO-1 TCR/IL-15 NK cells are safe in early studies. These specially designed cells target cancer cells while sparing healthy ones. Lab studies have demonstrated that these cells do not harm healthy human cells, such as those from the heart and lungs. Previous trials with similar engineered T-cells were well-tolerated, with no major safety issues.

The current trial is in its early stages, focusing mainly on finding a safe dose. Researchers closely monitor for any side effects. While some risks may exist, the treatment has generally been well-tolerated in studies so far. ^{1 2 3 4 5}

Why are researchers excited about this study treatment for multiple myeloma?

Researchers are excited about the NY-ESO-1 TCR/IL-15 NK cell therapy for multiple myeloma because it offers a novel approach by harnessing engineered immune cells. Unlike standard treatments like chemotherapy, immunomodulatory drugs, and proteasome inhibitors, this therapy uses modified natural killer (NK) cells that target the NY-ESO-1 antigen, which is often present in cancer cells. The therapy also includes interleukin-15 (IL-15) to enhance the survival and activity of these NK cells, potentially leading to a more effective attack on cancer cells. This targeted approach not only aims to improve effectiveness but might also reduce side effects compared to traditional therapies.

What evidence suggests that NY-ESO-1 TCR/IL-15 NK cells could be an effective treatment for multiple myeloma?

Research has shown that a new treatment using specially engineered cells, called NY-ESO-1 TCR/IL-15 NK cells, may help fight multiple myeloma, a type of cancer. These cells are designed to find and attack cancer cells. Participants in this trial will receive NY-ESO-1 TCR/IL-15 NK cells, either as an inpatient or outpatient treatment. Studies have found that these cells can remain active in the body, move to tumor sites, and continue to kill cancer cells over time. Early results suggest that these cells might help control the disease by enhancing the body's natural ability to fight cancer. While more research is needed, these initial findings offer hope for new treatment options. ^{1 2 3 5 6}

Who Is on the Research Team?

Muzaffar Qazilbash, MD

Principal Investigator

M.D. Anderson Cancer Center

Are You a Good Fit for This Trial?

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.

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

Interventions

• Cyclophosphamide
• Fludarabine phosphate
• NY-ESO-1 TCR/IL-15 NK cells

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.

How Is the Trial Designed?

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

NY-ESO-1 TCR/IL-15 NK cells is already approved in United States for the following indications:

Approved in United States as NY-ESO-1 TCR/IL-15 NK cells for:

• Relapsed/Refractory Multiple Myeloma
• Advanced Synovial Sarcoma
• Myxoid/Round Cell Liposarcoma

Who Is Running the Clinical Trial?

M.D. Anderson Cancer Center

Lead Sponsor

Trials

3,107

Recruited

1,813,000+

Published Research Related to This Trial

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]

Natural killer cells expanded from healthy donors and myeloma patients showed a significant ability to kill high-risk myeloma cells in vitro and in a mouse model, indicating their potential as a targeted therapy.

Adoptive transfer of these expanded natural killer cells not only inhibited myeloma tumor growth but also protected bone from damage caused by the disease, suggesting a dual benefit in treating myeloma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Highly activated and expanded natural killer cells for multiple myeloma immunotherapy. Garg, TK., Szmania, SM., Khan, JA., et al.[2021]

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]

The investigational drug NKTR-255, an IL-15 receptor agonist, effectively activates natural killer (NK) cells from multiple myeloma (MM) patients, enhancing their ability to recognize and kill MM cells, as shown by increased activating receptor expression and anti-tumor activity in vitro.

In vivo studies in humanized mice demonstrated that NKTR-255 not only increased circulating NK cells but also delayed tumor growth, and its combination with the anti-CD38 antibody daratumumab showed enhanced efficacy against MM, suggesting a promising therapeutic strategy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Improving NK cell function in multiple myeloma with NKTR-255, a novel polymer-conjugated human IL-15. Fernandez, RA., Mayoral, JE., Pierre-Louis, L., et al.[2023]

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]

NY-ESO-1 TCR-engineered T cells have demonstrated effectiveness in targeting solid tumors, particularly in multiple myeloma, by showing the ability to traffic to and persist in the bone marrow after infusion.

These T cells are well tolerated by patients and have produced promising response rates when administered following stem cell transplantation, indicating their potential as a therapeutic option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Engineering Anti-myeloma Responses Using Affinity-Enhanced TCR-Engineered T Cells. San Miguel, JF., Paiva, B., Lasarte, JJ.[2015]

Citations

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clinicaltrials.gov

clinicaltrials.gov/study/NCT06066359

NCT06066359 | Phase I/II Trial of Cord Blood-Derived NK ...

To learn if the dose of NY-ESO-1 TCR/IL-15 NK cells found in Part A can help to control the disease. Detailed Description. Primary Objectives: Part A: To assess ...

2.

cancer.gov

cancer.gov/research/participate/clinical-trials-search/v?id=NCI-2023-08318

Genetically Engineered Cells (NY-ESO-1 TCR/IL-15 NK ...

This phase I/II trial tests the safety, best dose, and effectiveness of NY-ESO-1 T-cell receptor (TCR)/IL-15 cord blood-derived natural killer (NK) cells

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pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC4529359/

NY-ESO-1 specific TCR engineered T-cells mediate ...

Our results Indicate that engineered cells engrafted long term, trafficked to sites of tumor, and retained polyfunctionality and cytotoxic potential over time, ...

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sparkcures.com

sparkcures.com/trial/1827/NCT06066359

Multiple Myeloma Support + Trials

What's 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.

5.

onclive.com

onclive.com/view/fda-clears-investigational-new-drug-application-for-tcr-nk-cell-therapy-in-multiple-myeloma

FDA Clears Investigational New Drug Application for TCR ...

The FDA has issued a 'safe to proceed' for the investigational new drug application enabling a phase 1 study evaluating NY-ESO-1 TCR/IL-15 NK.

6.

cgtlive.com

cgtlive.com/view/md-anderson-syena-tcr-nk-cell-therapy-another-ind-clearance-multiple-myeloma

MD Anderson and Syena's TCR NK Cell Therapy Gets ...

Notably, in preclinical IND-enabling studies, NY-ESO-1 TCR/IL-15 NK did not kill healthy human cells in cell lines derived from the heart, lungs ...