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

21 Participants Needed

Trial Summary

What is the purpose of this trial?

The goal of this clinical research study is to find the recommended dose of OBX-115 in combination with acetazolamide that can be given to patients with metastatic melanoma previously treated with immune checkpoint inhibitors. The safety and tolerability of the study drug combination will also be studied.

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.

What data supports the effectiveness of the treatment Engineered TILs + Acetazolamide for Melanoma?

Research shows that adoptive T-cell therapy using tumor-infiltrating lymphocytes (TIL) has achieved clinical response rates of 50% or more in metastatic melanoma patients, indicating its potential effectiveness. Additionally, gene-modified T-cells with enhanced properties have shown promising results in preclinical models, suggesting potential benefits for melanoma treatment. ^{1 2 3 4 5}

Is the treatment of Engineered TILs + Acetazolamide for Melanoma generally safe in humans?

The safety of engineered T cells, like those used in TIL therapy, has been studied, showing potential risks such as severe cytokine release syndrome (a severe immune reaction) and neurotoxicity (nerve damage). These risks highlight the importance of careful monitoring and management during treatment. ^{1 6 7 8 9}

What makes the treatment OBX-115 unique for melanoma?

OBX-115 is unique because it involves engineered tumor-infiltrating lymphocytes (TILs) that are modified to enhance their ability to target and kill melanoma cells, potentially offering a more effective approach than traditional therapies. This treatment also includes the use of acetazolamide, which may help improve the effectiveness of the TILs by modifying the tumor environment. ^{1 4 5 6 10}

Research Team

Rodabe N. Amaria

Principal Investigator

M.D. Anderson Cancer Center

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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]

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]

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]

References

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

Manufacture of gene-modified human T-cells with a memory stem/central memory phenotype. [2021]

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

White paper on adoptive cell therapy for cancer with tumor-infiltrating lymphocytes: a report of the CTEP subcommittee on adoptive cell therapy. [2020]

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

T cell receptor-engineered T cells to treat solid tumors: T cell processing toward optimal T cell fitness. [2018]

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

Antigen-dependent IL-12 signaling in CAR T cells promotes regional to systemic disease targeting. [2023]

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

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

6. France pubmed.ncbi.nlm.nih.gov

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

7. United States 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. [2023]

8. Ireland pubmed.ncbi.nlm.nih.gov

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

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

Cross-study safety analysis of risk factors in CAR T cell clinical trials: An FDA database pilot project. [2022]

10. England pubmed.ncbi.nlm.nih.gov

Antigen-dependent IL-12 signaling in CAR T cells promotes regional to systemic disease targeting. [2023]