Engineered TILs + Acetazolamide for Melanoma

Overseen By Rodabe N. Amaria

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: M.D. Anderson Cancer Center

Must not be taking: Steroids, Antineoplastics, Vaccines, others

Disqualifiers: Infections, Autoimmune, Cardiac, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: 8-12 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial seeks to determine the optimal dose of a new drug combination, OBX-115 (engineered tumor-infiltrating lymphocytes) with acetazolamide, for individuals with metastatic melanoma, a challenging-to-treat skin cancer that has spread. Researchers aim to assess the safety and tolerability of this combination, particularly in those who have previously tried treatments like immune checkpoint inhibitors. Individuals with metastatic melanoma who have undergone prior treatments but still require assistance may be suitable candidates for this trial. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new treatment.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, you cannot be on chronic steroid therapy above 10 mg/day of prednisone or its equivalent, and you must not have had chemotherapy or certain targeted therapies within 2 weeks before starting the trial.

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

Research has shown that OBX-115, when combined with acetazolamide, is generally well-tolerated by patients with advanced melanoma. Reports from an ongoing study indicate that patients can safely use this treatment at home, suggesting a lower risk of severe side effects compared to similar treatments.

Although the research remains in its early stages, these findings encourage those considering joining the trial. The combination of OBX-115 and acetazolamide aims to reduce side effects while maintaining effectiveness. Participants will be closely monitored to ensure their safety. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Researchers are excited about OBX-115 plus acetazolamide because this combination therapy offers a unique approach to treating melanoma. Unlike current treatments such as checkpoint inhibitors and targeted therapies, OBX-115 utilizes engineered tumor-infiltrating lymphocytes (TILs) which are designed to enhance the body's immune response specifically against melanoma cells. Additionally, acetazolamide is included to help improve the effectiveness of these TILs by altering the tumor environment to make it more favorable for the immune cells to attack. This innovative strategy could potentially lead to improved outcomes for patients with melanoma.

What evidence suggests that this trial's treatments could be effective for metastatic melanoma?

Research has shown that OBX-115 holds promise for treating advanced melanoma. OBX-115 is a therapy that uses special immune cells to attack cancer cells. Its unique design allows it to work effectively without IL-2, a common growth factor. In this trial, participants will receive a combination of OBX-115 and acetazolamide. Together, OBX-115 and acetazolamide have been well tolerated and have led to lasting responses against tumors, even in patients who did not respond to previous treatments. This combination aims to strengthen the body's immune response against melanoma tumors. ^{4 6 7 8 9}

Who Is on the Research Team?

Rodabe N. Amaria

Principal Investigator

M.D. Anderson Cancer Center

Are You a Good Fit for This Trial?

Adults over 18 with stage III or IV metastatic melanoma that's not removable by surgery and have failed immune checkpoint inhibitor therapy can join. They need a tumor for TIL generation, another for response assessment, proper organ function tests, no severe heart issues, and must use birth control. Excluded are those with uncontrolled illnesses, recent chemotherapy or live vaccines, certain infections like HIV/HCV requiring treatment, brain metastases of melanoma, serious cardiac conditions within the last 6 months, other cancers in the last 2 years (with exceptions), significant allergies to sulfa drugs or on chronic acetazolamide.

Inclusion Criteria

Within 7 days of tumor harvest and within 7 days of initiating lymphodepletion, patients must meet the following laboratory criteria: ANC ≥ 1000/mm3, Hemoglobin ≥ 8.0 g/dL (transfusion allowed), Platelet count ≥ 75,000/mm3, ALT/SGPT and AST/SGOT ≤ 2.5 x the upper limit of normal (ULN), Patients with liver metastases may have liver function tests (LFT) ≤ 5.0 x ULN, Calculated creatinine clearance (Cockcroft-Gault) ≥ 50.0 mL/min, Total bilirubin ≤ 1.5 X ULN, Negative serum pregnancy test (female patients of childbearing potential), 12-lead electrocardiogram (EKG) showing no active ischemia and Fridericia's corrected QT interval (QTcF) less than 480 ms, Echocardiogram showing no evidence of congestive heart failure (as defined by New York Heart Association Functional Classification III or IV) or LVEF <50%, Women of child-bearing potential (WCBP) must have a negative serum pregnancy test prior to treatment, Patients must have agreed to use effective methods of birth control throughout the study, Patient (or legally authorized representative) has voluntarily agreed to participate in the study by providing signed and dated informed consent (ICF) in accordance with International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines and applicable local regulations, Patient has agreed to abide by all protocol required procedures including study related assessments, and management by treating institution for the duration of the study and long-term follow-up (LTFU), Patients who have received bridging therapy between time of TIL harvest and initiation of lymphodepletion must meet all required clinical, laboratory and imaging criteria in order to qualify for therapy initiation, Lesions amenable to radiotherapy or palliative radiotherapy should be treated > 4 weeks prior to enrollment and subjects must be fully recovered from the effects of radiation. However, palliative radiation is permitted if subjects recover from all side effects to ≤ Grade 1 toxicities (based on CTCAE, v.5)

I am fully active or can carry out light work.

I have advanced melanoma with tumors that can be used to generate TILs and at least one tumor for tracking treatment response.

Exclusion Criteria

Patients who are pregnant or breastfeeding

I have not used immune checkpoint inhibitors as a temporary treatment.

I do not have a fever or an active infection needing treatment.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Chemotherapy

Participants receive chemotherapy to prepare the body for the study drug combination

2-3 weeks

Treatment

Participants receive OBX-115 and acetazolamide to assess safety, tolerability, and preliminary efficacy

8-12 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

12 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Acetazolamide
• OBX-115

Trial Overview This Phase I trial is testing OBX-115 combined with acetazolamide to find a safe dose for patients with metastatic melanoma who've already tried immune checkpoint inhibitors. It also includes pre-treatment drugs like cyclophosphamide and fludarabine phosphate to prepare the body ('lymphodepletion') before introducing OBX-115.

How Is the Trial Designed?

Group I: OBX-115 plus Acetazolamide Experimental Treatment 6 Interventions

Participants will receive chemotherapy to prepare your body for the study drug combination, then you will receive OBX-115 and acetazolamide.

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

CAR T cell therapy, particularly with CD19-targeting CARs like KYMRIAH™ and YESCARTA™, has shown high remission rates in patients with difficult-to-treat lymphomas, marking a significant advancement in cancer immunotherapy.

Despite their effectiveness, CAR T therapies can cause serious side effects such as cytokine release syndrome and neurotoxicity, prompting the need for improved safety measures and next-generation developments in the technology.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Next generation engineered T cells for cell therapy: from lymphoma to solid tumors]. Catros, V.[2019]

In a study involving 1,926 subjects from 17 clinical trials, patients with acute lymphocytic leukemia (ALL) were found to have a higher risk of severe cytokine release syndrome (sCRS) and severe neurological toxicities (sNTX) compared to those with non-Hodgkin's lymphoma (NHL) or multiple myeloma (MM).

The use of CAR T cells produced with gammaretrovirus vectors containing CD28 sequences was linked to increased rates of sNTX, while administering cytokine-directed therapies and corticosteroids at lower toxicity grades was associated with reduced rates of sCRS.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cross-study safety analysis of risk factors in CAR T cell clinical trials: An FDA database pilot project. Foster, M., Negash, Y., Eberhardt, L., et al.[2022]

CAR T cells engineered to target the tumor-associated glycoprotein-72 (TAG72) and modified with membrane-bound IL-12 (mbIL12) show enhanced anti-tumor activity and improved T cell proliferation, demonstrating significant efficacy in human ovarian cancer models.

The use of mbIL12 in CAR T cells not only promotes effective tumor cell killing but also positively impacts the immunosuppressive tumor microenvironment, suggesting a promising approach for treating both local and systemic cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antigen-dependent IL-12 signaling in CAR T cells promotes regional to systemic disease targeting. Lee, EHJ., Murad, JP., Christian, L., et al.[2023]

A new GMP protocol has been developed to produce T-cell receptor (TCR) gene-modified T-cells with an early memory phenotype, which may enhance their effectiveness in recognizing and attacking cancer cells.

These T-cells, generated using a combination of anti-CD3/CD28 stimulation and expansion with IL-7 and IL-15, are now being tested in a phase I/IIa clinical trial for advanced melanoma, marking a novel approach in T-cell therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Manufacture of gene-modified human T-cells with a memory stem/central memory phenotype. Gomez-Eerland, R., Nuijen, B., Heemskerk, B., et al.[2021]

In a study involving 16 healthy donors, researchers found that using specific activation conditions (soluble anti-CD3/CD28 mAbs with IL15 and IL21) improved the quality and function of gene-modified T cells, which is crucial for effective cancer treatment.

These optimized T cells showed better binding to target molecules and a more favorable phenotype, suggesting that these methods could enhance the efficacy of CAR and TCR therapies in future clinical trials for patients with certain tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

T cell receptor-engineered T cells to treat solid tumors: T cell processing toward optimal T cell fitness. Lamers, CH., van Steenbergen-Langeveld, S., van Brakel, M., et al.[2018]

The study developed optimized CAR T cells targeting TAG72, showing that the CD28 transmembrane domain enhances anti-tumor activity and IFNγ secretion, which is crucial for effective treatment of solid tumors like advanced ovarian cancer.

In preclinical models, CAR T cells expressing a membrane-bound IL-12 (mbIL12) significantly improved T cell proliferation and tumor cell killing, leading to strong anti-tumor responses and better T cell persistence, suggesting a promising approach for enhancing CAR T cell therapies in clinical settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antigen-dependent IL-12 signaling in CAR T cells promotes regional to systemic disease targeting. Jun Lee, EH., Cullen, C., Murad, JP., 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]

The study developed an affinity-enhanced T cell receptor (TCR) targeting the MAGE A3 antigen for cancer therapy, which showed promising preclinical results with no off-target effects; however, it led to a serious adverse event in patients, indicating potential safety risks.

Post-adverse event investigations revealed that the TCR also recognized a peptide from the muscle protein Titin, suggesting that off-target recognition can occur in vivo, emphasizing the need for improved preclinical testing methods to prevent such toxicities in future therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Identification of a Titin-derived HLA-A1-presented peptide as a cross-reactive target for engineered MAGE A3-directed T cells. Cameron, BJ., Gerry, AB., Dukes, J., et al.[2023]

Citations

1. onclive.com onclive.com/view/obx-115-with-acetazolamide-induces-safe-and-durable-antitumor-responses-in-advanced-melanoma

OBX-115 With Acetazolamide Induces Safe and Durable ... OBX-115 was well tolerated and produced durable antitumor responses in patients with immune checkpoint inhibitor (ICI)-resistant advanced melanoma.

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12436572/

Tumor-Infiltrating Lymphocyte Therapy for the Treatment of ... Because most TIL studies have focused on cutaneous melanoma, less is known about outcomes of TIL therapy in patients with these subtypes.

3. curemelanoma.org curemelanoma.org/blog/clinical-trials-to-watch-july-2025

Melanoma Clinical Trials to Watch: July 2025 Combinations of anti-PD1 drugs with other immune checkpoint drugs have been tested to see if they have better anti-tumor killing activity ...

4. clinicaltrials.gov clinicaltrials.gov/study/NCT05470283

NCT05470283 | Phase I, Open-Label, Study of Tumor ... Phase I, Open-Label, Study of Tumor Infiltrating Lymphocytes Engineered With Membrane Bound IL15 Plus Acetazolamide in Adult Patients With Metastatic Melanoma.

5. sciencedirect.com sciencedirect.com/science/article/pii/S266663672400784X

Review The Clinical TIL Experience in Melanoma The primary efficacy endpoints of complete response (CR) rate (24% vs. 24%) and median overall survival (38.2 vs. 36.6 months; hazard ratio [HR], 1.11; 95% ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT06060613

Safety and Efficacy of OBX-115 in Advanced Solid Tumors This is a study to investigate the safety and efficacy of an investigational OBX-115 regimen in adult participants with advanced solid tumors.

7. obsidiantx.com obsidiantx.com/news-releases/obsidian-therapeutics-announces-positive-clinical-data-from-obx-115-in-patients-with-advanced-melanoma-in-ongoing-multicenter-study-at-the-2025-american-society-of-clinical-oncology-asco-annual-meet/

News Summary of OBX-115 Safety and Efficacy Data (March 26, 2025 data cutoff): ... OBX-115 cells was tolerable and safe enough to administer at home.

8. clinicaltrials.cedars-sinai.edu clinicaltrials.cedars-sinai.edu/view/OBX115-23-01

OBX-115 in Unresectable or Metastatic Melanoma Researchers believe that giving these drugs together may result in less severe side effects and better effectiveness than those seen in other T cell therapies.

9. obsidiantx.com obsidiantx.com/our-lead-clinical-program/

OBX-115 | Investigational IL2-free TIL therapy with mbIL15 ... The primary objectives of the trial are to assess the safety, tolerability, and preliminary efficacy of the OBX-115 TIL cell therapy regimen in patients with ...