OBX-115 for Skin Cancer

(Agni-01 Trial)

Recruiting at 16 trial locations

Overseen By Obsidian Therapeutics

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Obsidian Therapeutics, Inc.

Must not be taking: Systemic steroids

Disqualifiers: Brain metastases, Immunodeficiency, Organ transplant, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: 4 weeks

52 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial tests a new treatment called OBX-115 for adults with advanced solid tumors. It aims to see if the treatment is safe and effective by measuring its ability to shrink tumors, control disease progression, and improve survival.

Will I have to stop taking my current medications?

The trial information does not specify if you need to stop taking your current medications. However, if you are on systemic steroid therapy greater than 10 mg/day of prednisone or equivalent, you may not be eligible to participate.

What data supports the effectiveness of the treatment OBX-115 for skin cancer?

Research shows that IL15, a component of the treatment, can boost the immune system's T-cells and natural killer cells, which are important for fighting cancer. This has been effective in other cancer treatments, suggesting potential benefits for skin cancer as well. ^{1 2 3 4 5}

What safety data exists for OBX-115 or similar treatments in humans?

CAR T-cell therapies, like OBX-115, have shown significant potential in treating various cancers but can cause serious side effects such as cytokine release syndrome (CRS) and neurological toxicities. These treatments are being improved with safety measures like the inducible Caspase 9 'safety switch' to manage these risks. ^{6 7 8 9 10}

What makes the OBX-115 treatment for skin cancer unique?

OBX-115 is unique because it uses genetically modified T cells that include IL-15, a powerful immune stimulator, to enhance the persistence and effectiveness of the T cells in fighting cancer, potentially reducing toxicity compared to other treatments. ^{1 2 6 11 12}

Eligibility Criteria

Adults with advanced melanoma resistant to immune checkpoint inhibitors can join. They must have had disease progression after specific systemic therapies, at least one resectable lesion for OBX-115 generation, and be in good health otherwise. Participants need proper organ function, an ECOG status of 0 or 1, and agree to use contraception.

Inclusion Criteria

My cancer progressed after treatment with PD-1/PD-L1 inhibitors and, if applicable, BRAF/MEK inhibitors.

I have at least one tumor that can be measured after a biopsy.

I can care for myself and doctors expect me to live more than 6 months.

Exclusion Criteria

You have a weakened immune system, either from birth or from getting sick.

I have had cancer spread to my brain or its coverings.

I need more than 10 mg/day of prednisone or a similar medication.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Conditioning Therapy

Participants receive conditioning therapy prior to administration of OBX-115 regimen

1-2 weeks

Treatment

Participants receive the OBX-115 regimen and are monitored for dose-limiting toxicities

4 weeks

Weekly visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment, including assessment of response and adverse events

2 years

Treatment Details

Interventions

• OBX-115

Trial Overview The trial is testing the safety and effectiveness of a new treatment called OBX-115 on adults with advanced melanoma that hasn't responded to previous treatments including PD-1/PD-L1 blockers and possibly BRAF/MEK inhibitors.

Participant Groups

Group I: Participants with advanced solid tumors Experimental Treatment 1 Intervention

Participants will receive conditioning therapy prior to administration of OBX-115 regimen.

Who Is Running the Clinical Trial?

Obsidian Therapeutics, Inc.

Lead Sponsor

Trials

1

Recruited

50+

Findings from Research

IL15 is a powerful cytokine that enhances the immune response by boosting T-cells and natural killer (NK) cells, showing promise for improving cancer treatments through adoptive T-cell transfer.

Clinical trials have demonstrated that IL15 can significantly increase the activity of NK and CD8(+) memory T cells, suggesting its potential as a key component in T-cell-based immunotherapy for cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

IL15 and T-cell Stemness in T-cell-Based Cancer Immunotherapy. Pilipow, K., Roberto, A., Roederer, M., et al.[2021]

CAR-T cells engineered to overexpress IL-15 showed improved viability and anti-tumor effects, but also led to serious liver injuries and lower survival rates in mouse models, indicating potential toxicity issues.

Combining IL-15 with IL-15 receptor alpha (IL-15Ra) in CAR-T cells reduced cytokine release and improved mouse survival while still effectively inhibiting tumor growth, suggesting a way to enhance the safety and efficacy of CAR-T therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Co-expression IL-15 receptor alpha with IL-15 reduces toxicity via limiting IL-15 systemic exposure during CAR-T immunotherapy. Zhang, Y., Zhuang, Q., Wang, F., et al.[2022]

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]

High doses of interleukin-2 and various experimental immunotherapy strategies can lead to prolonged responses in patients with metastatic melanoma, indicating their potential effectiveness in treatment.

The development of these immunotherapy approaches is based on a deeper understanding of immune system activation, which may enhance the ability to target tumors and improve patient outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Update on immunotherapy for melanoma. Ribas, A.[2019]

The study identified a second-generation CAR targeting MCSP that showed higher and more prolonged expression in T cells, leading to improved anti-tumor activity against melanoma cells.

T cells modified with this CAR not only increased survival in mice with melanoma but also effectively lysed tumor cells and released pro-inflammatory cytokines after being transfected from late-stage melanoma patients, suggesting strong potential for clinical application.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Stability and activity of MCSP-specific chimeric antigen receptors (CARs) depend on the scFv antigen-binding domain and the protein backbone. Krug, C., Birkholz, K., Paulus, A., et al.[2015]

The study developed a novel CAR T cell therapy targeting the MUC-16ecto antigen in ovarian cancer, showing that the addition of IL-12 enhances T cell proliferation and IFNγ secretion, leading to improved antitumor efficacy in mouse models.

To ensure safety in potential clinical applications, the CAR T cells include an elimination gene that allows for their removal in case of unexpected side effects, making this approach both innovative and cautious.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

IL-12 secreting tumor-targeted chimeric antigen receptor T cells eradicate ovarian tumors in vivo. Koneru, M., Purdon, TJ., Spriggs, D., et al.[2021]

The study successfully developed a rapid 2-week protocol to create neoantigen-specific TCR-engineered T cells from ovarian cancer patients, demonstrating the feasibility of this approach for advanced cancers.

While the engineered T cells showed effective cytotoxic activity against neoantigens, one case exhibited cross-reactivity with a wild-type peptide, highlighting the need for careful validation to prevent potential immune-related side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Induction of Neoantigen-Specific Cytotoxic T Cells and Construction of T-cell Receptor-Engineered T Cells for Ovarian Cancer. Matsuda, T., Leisegang, M., Park, JH., et al.[2022]

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 therapy has shown significant success in treating relapsed/refractory B-cell malignancies, utilizing genetically modified T-cells to target and eliminate cancer cells effectively.

Despite its efficacy, CAR-T therapy is associated with serious toxicities such as cytokine release syndrome and neurotoxicity, necessitating improved safety measures, especially as the therapy is being tested in solid tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Building safety into CAR-T therapy. Peters, DT., Savoldo, B., Grover, NS.[2023]

The CAR-HEMATOTOX (HT) score effectively identifies patients at high risk for severe infections after CD19 CAR-T therapy, with high-risk patients experiencing a significantly higher rate of severe infections (40% vs 8%) and worse survival outcomes.

Prophylactic antibacterial treatment significantly reduced severe bacterial infections in high-risk patients, highlighting the importance of monitoring and preventive care for those identified as high risk before undergoing CAR-T therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The CAR-HEMATOTOX risk-stratifies patients for severe infections and disease progression after CD19 CAR-T in R/R LBCL. Rejeski, K., Perez, A., Iacoboni, G., et al.[2022]

This study shows that tumor infiltrating lymphocytes (TIL) and effusion-associated mononuclear cells (EAMNC) from breast cancer patients can be significantly expanded in vitro using recombinant interleukin-2 (rIL-2), achieving over 300-fold proliferation while retaining their ability to target and kill autologous tumor cells.

The activated CD3+CD8+ T-lymphocytes demonstrated specific cytotoxicity against the patient's own tumor cells, indicating their potential for use in immunotherapy for advanced breast cancer, as they maintain both autologous tumor-specific and MHC-restricted cytotoxic activity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tumor specific cytolysis by tumor infiltrating lymphocytes in breast cancer. Baxevanis, CN., Dedoussis, GV., Papadopoulos, NG., et al.[2019]

Incorporating the IL15 cytokine into the CAR construct (GD2.CAR.15) significantly enhances the survival and antitumor activity of T cells against neuroblastoma, showing improved performance compared to the standard GD2.CAR-T cells in both laboratory and animal models.

The engineered GD2.CAR.15-T cells exhibited reduced PD-1 expression and a stem cell-like phenotype, which contributed to their superior effectiveness, while also including a safety switch (iC9) that allows for controlled elimination of these cells if necessary.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Eradication of Neuroblastoma by T Cells Redirected with an Optimized GD2-Specific Chimeric Antigen Receptor and Interleukin-15. Chen, Y., Sun, C., Landoni, E., et al.[2020]

References

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

IL15 and T-cell Stemness in T-cell-Based Cancer Immunotherapy. [2021]

2. England pubmed.ncbi.nlm.nih.gov

Co-expression IL-15 receptor alpha with IL-15 reduces toxicity via limiting IL-15 systemic exposure during CAR-T immunotherapy. [2022]

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

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

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

Update on immunotherapy for melanoma. [2019]

5. Germany pubmed.ncbi.nlm.nih.gov

Stability and activity of MCSP-specific chimeric antigen receptors (CARs) depend on the scFv antigen-binding domain and the protein backbone. [2015]

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

IL-12 secreting tumor-targeted chimeric antigen receptor T cells eradicate ovarian tumors in vivo. [2021]

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

Induction of Neoantigen-Specific Cytotoxic T Cells and Construction of T-cell Receptor-Engineered T Cells for Ovarian Cancer. [2022]

8. 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]

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

Building safety into CAR-T therapy. [2023]

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

The CAR-HEMATOTOX risk-stratifies patients for severe infections and disease progression after CD19 CAR-T in R/R LBCL. [2022]

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

Tumor specific cytolysis by tumor infiltrating lymphocytes in breast cancer. [2019]

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

Eradication of Neuroblastoma by T Cells Redirected with an Optimized GD2-Specific Chimeric Antigen Receptor and Interleukin-15. [2020]