NK Cell Therapy + Chemotherapy for Sarcoma

Overseen By John Livingston, MD

Age: Any Age

Sex: Any

Trial Phase: Phase 1

Sponsor: M.D. Anderson Cancer Center

Must not be taking: Steroids, Immunosuppressants, Anticancer agents

Disqualifiers: Infections, Hepatitis, HIV, Autoimmune, 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

Duration: 4-6 weeks

44 Participants Needed

Trial Summary

What is the purpose of this trial?

The goal of this clinical research study is to find a recommended dose of donated NK cells that can be given along with chemotherapy to patients with advanced cancers. The safety and effects of this therapy will also be studied.

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

The trial requires that you stop taking certain medications before starting. You must be at least 2 weeks from your last chemotherapy and stop any tyrosine kinase inhibitors or targeted therapies at least 3 days before starting the trial's chemotherapy. If you're on systemic steroids, you may need to adjust your dose.

What data supports the effectiveness of the treatment NK Cell Therapy + Chemotherapy for Sarcoma?

Research shows that T-cell therapies targeting NY-ESO-1, a protein found in some sarcomas, have been effective in treating advanced soft tissue sarcomas. In a clinical trial, patients receiving a similar treatment had a 41.7% response rate, with a median progression-free survival of 7.2 months. ^{1 2 3 4 5}

Is NK Cell Therapy + Chemotherapy for Sarcoma safe for humans?

Research shows that treatments involving NY-ESO-1-specific TCR T cells, combined with chemotherapy drugs like cyclophosphamide and fludarabine, have been tested in humans with advanced soft tissue sarcoma. These studies found no serious treatment-related side effects, indicating that the therapy is generally safe. ^{1 3 4 5 6}

What makes the NK Cell Therapy + Chemotherapy for Sarcoma treatment unique?

This treatment is unique because it combines NK (natural killer) cells engineered to target the NY-ESO-1 protein, which is often found in sarcoma cells, with chemotherapy. This approach leverages the body's immune system to specifically attack cancer cells, potentially offering a more targeted and effective treatment compared to traditional therapies. ^{3 6 7 8 9}

Research Team

John A Livingston, MD MS

Principal Investigator

M.D. Anderson Cancer Center

Eligibility Criteria

This trial is for people aged 16-80 with advanced sarcomas, specifically synovial or myxoid/round cell liposarcoma, who've tried at least one standard treatment without success. They must have proper liver, kidney, heart, and blood function and no serious infections or autoimmune diseases. Participants need to be HLA-A*02 positive with NY-ESO-1 expression in tumors.

Inclusion Criteria

My organs are functioning well according to my recent tests.

My cancer expresses NY-ESO-1 and I have specific HLA types.

My cancer is either synovial sarcoma or myxoid/round cell liposarcoma, tests positive for specific HLA types, and shows high NY-ESO-1 expression.

Exclusion Criteria

- Uncontrolled arrhythmia, considered per PI

I have an active neurological disorder.

I have serious side effects from past cancer treatment.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Lymphodepleting Chemotherapy

Participants receive lymphodepleting chemotherapy prior to NK cell infusion

1-2 weeks

Treatment

Participants receive adoptive NK cells expressing an affinity-enhanced T-cell receptor (TCR) reactive against the NY-ESO-1

4-6 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

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

Trial Overview The study tests the safety and optimal dose of donated NK cells expressing a TCR against NY-ESO-1 combined with chemotherapy (Cyclophosphamide and Fludarabine phosphate) in patients with specific advanced cancers to see how well they tolerate it and its effects on their disease.

Participant Groups

Group I: Dose escalation - Inpatient and Outpatient Experimental Treatment 3 Interventions

Participants will be assigned to receive a dose level of NK cells based on when the participants joins the study. Up to 6 participants will be enrolled at each dose level. If no intolerable side effects are seen after the first 3-6, the next group of participants will get at higher dose. Up to 4 dose levels of NK cells will be tested. If the first dosing group shows intolerable side effects, a lower dose will be tested.

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

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

• Multiple Myeloma
• 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+

Findings from Research

In a study involving 8 patients with advanced or recurrent synovial sarcoma, the infusion of autologous T lymphocytes expressing NY-ESO-1 T-cell receptors showed a promising objective response rate of 50%, indicating potential efficacy in targeting this type of cancer.

While all patients experienced adverse events, the treatment was considered safe, with no deaths linked to these events and manageable cases of cytokine release syndrome, suggesting that TBI-1301 could be a viable option for patients resistant to standard therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and Efficacy of NY-ESO-1 Antigen-specific T-cell Receptor Gene-Transduced T Lymphocytes in Patients with Synovial Sarcoma: A Phase I/II Clinical Trial. Kawai, A., Ishihara, M., Nakamura, T., et al.[2023]

A 68-year-old man with synovial sarcoma showed a 34.9% reduction in tumor size after TCR-T therapy targeting the NY-ESO-1 protein, but disease progression occurred shortly after treatment, highlighting the challenge of resistance to TCR-T therapy.

The study found that beta-catenin levels were up-regulated in recurrent tumor tissues after TCR-T therapy, suggesting it may play a role in T-cell exclusion and resistance, indicating a potential area for further research in improving TCR-T efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Histological Assessment of Synovial Sarcoma Before and After TCR-T Cell Therapy and Cryoablation: A Case Report. Asanuma, K., Ishihara, M., Nakamura, T., et al.[2023]

The phase 1 trial showed that NY-ESO-1-specific TCR-T cells are both safe and effective for treating advanced soft tissue sarcomas, marking a significant advancement in adoptive T cell therapy.

This study represents an important step in the clinical application of T cell therapies, potentially offering new hope for patients with this challenging type of cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pushing forward in sarcoma with a new TCR targeting NY-ESO-1. Al-Marayaty, R., Pollack, SM.[2023]

The phase 1 clinical trial of TAEST16001, a TCR affinity-enhanced T cell therapy targeting NY-ESO-1, showed no serious treatment-related adverse events in 12 patients, indicating a safe therapeutic approach.

The therapy demonstrated an overall response rate of 41.7%, with a median progression-free survival of 7.2 months and a median duration of response of 13.1 months, highlighting its efficacy in treating advanced soft tissue sarcoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase 1 clinical trial to assess safety and efficacy of NY-ESO-1-specific TCR T cells in HLA-A∗02:01 patients with advanced soft tissue sarcoma. Pan, Q., Weng, D., Liu, J., et al.[2023]

In a phase I clinical trial involving four patients with synovial sarcoma and myxoid/round cell liposarcoma, NY-ESO-1-specific endogenous T cell therapy was well tolerated without significant toxicity, although all patients experienced disease progression.

Despite the presence of NY-ESO-1-specific T cells in the blood, these cells showed limited activation and proliferation; however, they could be stimulated to become active using IL-15, suggesting a potential strategy to enhance the effectiveness of adoptive cellular therapy in future treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

IL-15 mediated expansion of rare durable memory T cells following adoptive cellular therapy. Kohli, K., Yao, L., Nowicki, TS., et al.[2022]

Transgenic adoptive cell therapy (ACT) using NY-ESO-1-specific T cells combined with dendritic cell vaccination showed promising results, with 66% of patients in the ESO cohort and 50% in the INY cohort experiencing tumor regression.

The study indicated that while the combination of ACT and dendritic cell vaccination is feasible and leads to some antitumor activity, adding the immune checkpoint inhibitor ipilimumab did not provide additional clinical benefits, suggesting that further improvements are needed to sustain tumor responses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Pilot Trial of the Combination of Transgenic NY-ESO-1-reactive Adoptive Cellular Therapy with Dendritic Cell Vaccination with or without Ipilimumab. Nowicki, TS., Berent-Maoz, B., Cheung-Lau, G., et al.[2023]

In a study involving 190 sarcoma tumor specimens, researchers successfully isolated tumor-infiltrating lymphocytes (TILs) from 54 of 92 primary sarcoma samples, indicating that certain sarcoma subtypes can provide enough TILs for potential immunotherapy.

The optimized protocol for expanding TILs demonstrated that these cells retained their ability to react and release IFNγ upon stimulation, suggesting their viability for future personalized immunotherapy treatments in sarcoma patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Investigating the Potential of Isolating and Expanding Tumour-Infiltrating Lymphocytes from Adult Sarcoma. Ko, A., Coward, VS., Gokgoz, N., et al.[2022]

Ewing sarcoma (EWS) cells are susceptible to natural killer (NK) cell-mediated lysis, especially when NK cells are activated with interleukin-15 (IL-15), indicating a potential for immunotherapy in treating this cancer.

The effectiveness of NK cell cytotoxicity against EWS is primarily driven by the activation signals from receptors NKG2D and DNAM-1, suggesting that enhancing these pathways could improve therapeutic outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

NK cells recognize and lyse Ewing sarcoma cells through NKG2D and DNAM-1 receptor dependent pathways. Verhoeven, DH., de Hooge, AS., Mooiman, EC., et al.[2021]

Combining NY-ESO-1-specific T cells with histone deacetylase inhibitors (HDACis) like panobinostat or vorionstat enhances the effectiveness of these T cells against soft tissue sarcoma (STS) cells, as shown in ex vivo studies.

Pretreatment with HDACis increases the expression of the NY-ESO-1 antigen and HLA-ABC on STS cells, leading to improved T cell activation and cytokine release, suggesting a promising strategy to boost the efficacy of adoptive cell therapy in treating STS.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

HDAC Inhibition for Optimized Cellular Immunotherapy of NY-ESO-1-Positive Soft Tissue Sarcoma. Gong, W., Wang, L., Schubert, ML., et al.[2022]

References

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

Safety and Efficacy of NY-ESO-1 Antigen-specific T-cell Receptor Gene-Transduced T Lymphocytes in Patients with Synovial Sarcoma: A Phase I/II Clinical Trial. [2023]

2. Greece pubmed.ncbi.nlm.nih.gov

Histological Assessment of Synovial Sarcoma Before and After TCR-T Cell Therapy and Cryoablation: A Case Report. [2023]

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

Pushing forward in sarcoma with a new TCR targeting NY-ESO-1. [2023]

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

Phase 1 clinical trial to assess safety and efficacy of NY-ESO-1-specific TCR T cells in HLA-A∗02:01 patients with advanced soft tissue sarcoma. [2023]

5. England pubmed.ncbi.nlm.nih.gov

IL-15 mediated expansion of rare durable memory T cells following adoptive cellular therapy. [2022]

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

A Pilot Trial of the Combination of Transgenic NY-ESO-1-reactive Adoptive Cellular Therapy with Dendritic Cell Vaccination with or without Ipilimumab. [2023]

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

Investigating the Potential of Isolating and Expanding Tumour-Infiltrating Lymphocytes from Adult Sarcoma. [2022]

8. England pubmed.ncbi.nlm.nih.gov

NK cells recognize and lyse Ewing sarcoma cells through NKG2D and DNAM-1 receptor dependent pathways. [2021]

9. Switzerland pubmed.ncbi.nlm.nih.gov

HDAC Inhibition for Optimized Cellular Immunotherapy of NY-ESO-1-Positive Soft Tissue Sarcoma. [2022]