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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment involving engineered immune cells designed to target melanoma, a type of skin cancer that has returned or is unresponsive to other treatments. The goal is to determine the safest and most effective dose of these engineered cells. Participants will either join a group testing increasing doses or receive a set dose once deemed safe. This trial may suit those with advanced melanoma who have tried standard treatments without success and have a specific immune system marker (HLA A*02:01). As a Phase 1 trial, this research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this innovative therapy.

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.

Is there any evidence suggesting that PRAME-TCR-NK cells are likely to be safe for humans?

Research has shown that PRAME TCR NK cells, a new type of engineered therapy, have been safe in lab tests and early human studies. These studies aim to find the best dose that people can handle without harmful effects. The FDA has approved moving forward with testing in humans, indicating it is considered safe enough. Although still in the early stages, this treatment is closely monitored to determine the safest and most effective way to use it for people with difficult-to-treat melanoma. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Researchers are excited about PRAME-TCR-NK cells for melanoma because they represent a novel approach to cancer treatment. Unlike traditional therapies like chemotherapy and immunotherapy, which can affect healthy cells and often have broad mechanisms, PRAME-TCR-NK cells are engineered to specifically target and attack melanoma cells expressing the PRAME antigen. This precision reduces potential damage to healthy cells and aims to enhance effectiveness. Additionally, this treatment utilizes NK (natural killer) cells, which are known for their ability to directly kill cancer cells, potentially offering a more powerful and targeted attack on melanoma tumors.

What evidence suggests that PRAME-TCR-NK cells might be an effective treatment for melanoma?

Studies have shown that PRAME TCR NK cells hold promise in fighting melanoma, a type of skin cancer. These specially designed cells have succeeded in lab and animal tests, demonstrating their ability to locate and destroy melanoma cells. Early results suggest this treatment might be safe for humans, as tests have not revealed major safety issues. In this trial, participants will receive PRAME-TCR-NK cells, with the dose depending on the study phase they join. Researchers believe this method could help treat melanoma that hasn't responded to other treatments. The treatment uses modified immune cells to more effectively find and attack cancer cells. ^{1 3 4 6 7}

Who Is on the Research Team?

Isabella C Glitza Oliva, MD

Principal Investigator

M.D. Anderson Cancer Center

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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 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]

Citations

1. ascopubs.org ascopubs.org/doi/10.1200/JCO.2025.43.16_suppl.TPS9602

Phase I dose escalation and expansion study of PRAME T- ... PRAME TCR/IL-15 NK, an engineered TCR NK cell therapy, has demonstrated efficacy against melanoma cell lines in vitro and in vivo and safety ...

2. cancer.gov cancer.gov/research/participate/clinical-trials-search/v?id=NCI-2024-08948

PRAME-TCR-NK Cells for the Treatment of Patients with ... Giving PRAME-TCR-NK cells may be safe, tolerable, and/or effective in treating patients with locally advanced, metastatic, unresectable, recurrent and/or ...

3. clinicaltrials.gov clinicaltrials.gov/study/NCT06660420

Phase 1 Dose Escalation and Expansion Study of PRAME ... 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.

4. nature.com nature.com/articles/s41591-025-03650-6

Autologous T cell therapy for PRAME + advanced solid ... Here we report interim data from a first-in-human, multicenter, open-label, 3 + 3 dose-escalation/de-escalation phase 1 trial studying IMA203, ...

5. withpower.com withpower.com/trial/phase-1-phase-1-3-2025-4b766

PRAME-TCR-NK Cells for Melanoma Adoptive T-cell therapy using tumor-infiltrating lymphocytes (TILs) has shown significant promise in treating metastatic melanoma, leading to the development of ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT06660420

Phase 1 Dose Escalation and Expansion Study of PRAME ... 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.

7. mdanderson.org mdanderson.org/newsroom/novel-PRAME-targeted-TCR-NK-cell-therapy-receives-FDA-IND-clearance-hematologic-cancers.h00-159696756.html

Novel PRAME-targeted TCR NK cell therapy receives FDA ... The Food & Drug Administration (FDA) has issued a 'safe to proceed' for the Investigational New Drug (IND) application for PRAME TCR/IL-15 NK (SY-307).