PRAME-TCR-NK Cells for Melanoma

Overseen By Isabella C Glitza Oliva, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: M.D. Anderson Cancer Center

Must not be taking: Steroids, Immunosuppressants

Disqualifiers: Pregnancy, Immunodeficiency, Active infection, others

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

Compensation: Varies

Number of Visits: Unknown

39 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial protocol does not specify if you need to stop taking your current medications. However, you must not have received systemic anticancer therapy within 2 weeks or 5 half-lives before starting the trial's chemotherapy, and monoclonal antibody treatments must be stopped at least 3 weeks prior.

What data supports the effectiveness of the treatment PRAME T Cell Receptor (TCR) Engineered NK Cells for melanoma?

Research shows that engineered NK cells, which are a type of immune cell, can be modified to specifically target and kill melanoma cells. In studies, these modified NK cells have demonstrated enhanced ability to recognize and destroy melanoma cells, both in laboratory settings and in animal models, suggesting they could be a promising treatment for melanoma. ^{1 2 3 4 5}

Is PRAME-TCR-NK cell therapy safe for humans?

Research on engineered T cells and NK cells for cancer treatment, including melanoma, highlights safety concerns such as potential severe side effects like cytokine release syndrome (a severe immune reaction) and neurologic toxicities. Efforts are ongoing to improve safety by carefully selecting target antigens and developing strategies to reduce these risks. ^{1 3 6 7 8}

How is the PRAME-TCR-NK Cells treatment for melanoma different from other treatments?

The PRAME-TCR-NK Cells treatment is unique because it uses genetically engineered natural killer (NK) cells that are modified to express a T-cell receptor (TCR), allowing them to specifically target and kill melanoma cells. This approach combines the innate ability of NK cells to attack tumors with the specificity of TCRs, potentially offering a more targeted and effective treatment compared to traditional therapies. ^{1 2 9 10 11}

What is the purpose of this trial?

To find the highest tolerable dose and recommended dose of PRAME-TCR-NK cells that can be given to participants with recurrent and/or refractory melanoma. The safety and tolerability of PRAME-TCR-NK cells will also be studied.

Research Team

Isabella C Glitza Oliva, MD

Principal Investigator

M.D. Anderson Cancer Center

Eligibility Criteria

This trial is for people with melanoma that has come back or hasn't responded to treatment. Participants must meet certain health requirements, which will be specified by the researchers conducting the study.

Inclusion Criteria

I am willing to have blood tests and biopsies.

Participants must have measurable disease per the Response Evaluation Criteria in Solid Tumors (RECIST)

I agree not to get a live vaccine for 2 years after my treatment.

Exclusion Criteria

Not recovered from all adverse events due to previous therapies

Psychiatric or substance abuse disorders that would interfere with study cooperation

I have had another type of cancer in the past 2 years.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Escalation Phase

Participants receive PRAME-TCR-NK cells at varying doses to determine the maximum tolerated dose

8-12 weeks

Expansion Phase

Participants receive PRAME-TCR-NK cells at the recommended dose along with fludarabine and cyclophosphamide

8-12 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• PRAME T Cell Receptor (TCR) Engineered NK Cells

Trial Overview Researchers are testing PRAME-TCR-NK cells at various doses to find the highest dose patients can tolerate without severe side effects. They're also looking for a recommended safe dose and assessing overall safety.

Participant Groups

Group I: Expansion Phase Experimental Treatment 2 Interventions

Participants will receive PRAME-TCR-NK cells at the recommended dose.All participants will receive the same dose level of fludarabine and cyclophosphamide

Group II: Escalation Phase Experimental Treatment 2 Interventions

The dose of PRAME-TCR-NK cells you receive will depend on when you join this study. Up to 5 dose levels of the study product will be tested. The first group of participants will receive the lowest dose level of the study product. Each new group will receive a higher dose of the study product than the group before it, if no intolerable side effects were seen. This will continue until the highest tolerable dose and recommended dose of the study product is found.

Who Is Running the Clinical Trial?

M.D. Anderson Cancer Center

Lead Sponsor

Trials

3,107

Recruited

1,813,000+

Findings from Research

Engineered T cells with an affinity-enhanced T-cell receptor (TCR) against MAGE-A3 led to severe cardiogenic shock and death in two patients, indicating serious and unpredictable off-target effects despite preclinical safety assessments.

Autopsy results showed significant heart damage and T-cell infiltration, but no MAGE-A3 expression was found in heart tissues, suggesting that the T cells may have targeted an unrelated peptide from a muscle protein, highlighting the need for better specificity testing in TCR engineering.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cardiovascular toxicity and titin cross-reactivity of affinity-enhanced T cells in myeloma and melanoma. Linette, GP., Stadtmauer, EA., Maus, MV., et al.[2023]

Adoptive T-cell therapy using tumor-infiltrating lymphocytes (TILs) has shown significant promise in treating metastatic melanoma, leading to the development of genetically engineered T cells that can specifically target tumor-associated antigens (TAAs).

Initial clinical studies indicate that these genetically engineered T cells, including those with tumor antigen-specific T cell receptors (TCRs) and chimeric antigen receptors (CARs), can effectively cause tumor regression, although safety concerns, particularly regarding potential 'on-target, off-organ' toxicity, must be carefully managed.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Improving the efficacy and safety of engineered T cell therapy for cancer. Shi, H., Liu, L., Wang, Z.[2020]

Engineered natural killer T cells (NKT) expressing a functional T-cell receptor (TCR) demonstrated effective antitumor activity in mouse models without causing graft-versus-host disease, suggesting a safer alternative for adoptive T-cell therapy.

The study revealed that the engineered TCR can displace the invariant TCR (iTCR) in NKT cells, allowing for effective targeting of cancer cells while minimizing the risk of autoreactivity, making these cells promising candidates for 'off-the-shelf' immunotherapy products.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A High-Avidity T-cell Receptor Redirects Natural Killer T-cell Specificity and Outcompetes the Endogenous Invariant T-cell Receptor. Landoni, E., Smith, CC., Fucá, G., et al.[2020]

A new cell line was developed that lacks endogenous T cell receptors, allowing for the rapid generation of homogeneous cells to evaluate T cell receptor (TCR) activity more efficiently.

The engineered Natural Killer (NK) cells expressing human CD3 and interleukin-2 demonstrated similar cytotoxic effects and cytokine production as primary TCR-transduced T cells, making them a promising tool for assessing TCR functions in cancer immunotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Gene modified NK cell line as a powerful tool for evaluation of cloned TCRs for TCR-T cell therapy. Kobayashi, E., Ozawa, T., Hamana, H., et al.[2023]

References

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

Retargeting NK-92 for anti-melanoma activity by a TCR-like single-domain antibody. [2018]

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

Genetically Engineered Natural Killer Cells as a Means for Adoptive Tumor Immunotherapy. [2018]

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

Engineering Natural Killer Cells for Cancer Immunotherapy. [2023]

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

Cardiovascular toxicity and titin cross-reactivity of affinity-enhanced T cells in myeloma and melanoma. [2023]

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

Engineering antigen-specific primary human NK cells against HER-2 positive carcinomas. [2020]

6. Ireland pubmed.ncbi.nlm.nih.gov

Improving the efficacy and safety of engineered T cell therapy for cancer. [2020]

7. Denmark pubmed.ncbi.nlm.nih.gov

Fasten the seat belt: Increasing safety of CAR T-cell therapy. [2021]

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

Endowing universal CAR T-cell with immune-evasive properties using TALEN-gene editing. [2022]

9. Germany pubmed.ncbi.nlm.nih.gov

TCR extracellular domain genetically linked to CD28, 2B4/41BB and DAP10/CD3ζ -engineered NK cells mediates antitumor effects. [2023]

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

A High-Avidity T-cell Receptor Redirects Natural Killer T-cell Specificity and Outcompetes the Endogenous Invariant T-cell Receptor. [2020]

11. Netherlands pubmed.ncbi.nlm.nih.gov

Gene modified NK cell line as a powerful tool for evaluation of cloned TCRs for TCR-T cell therapy. [2023]