Adoptive Cell Therapy for Melanoma

(ACT Trial)

Overseen By Ryan D Montler, MBA

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: AgonOx, Inc.

Must not be taking: Corticosteroids, Immunosuppressives

Disqualifiers: Active brain metastases, Autoimmune disease, others

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

Compensation: Varies

Number of Visits: Unknown

18 Participants Needed

Trial Summary

What is the purpose of this trial?

The subject of this study is the adoptive transfer of selected autologous tumor infiltrating lymphocytes (TIL) after in vitro expansion for the treatment of solid tumor malignancies. The TIL selection process is based on evidence showing that CD8+ TIL which co-express both CD39 and CD103 harbor the bulk of tumor-reactivity and that the remaining CD8 TIL is mainly composed of non-tumor reactive bystander cells. All of the expanded TIL that are produced (1-40 billion are expected) will be delivered in the form of a cell suspension to the participants by intravenous infusion. It is proposed that these selected TIL will produce a more potent and efficacious treatment of late-stage cancer.

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop taking your current medications. However, you cannot participate if you require certain immunosuppressive medications or have had recent chemotherapy, radiotherapy, or other antitumor treatments within 2 weeks of the study start.

What data supports the effectiveness of the treatment Adoptive Cell Therapy for Melanoma?

Research shows that adoptive cell therapy using tumor-infiltrating lymphocytes (TIL) can lead to significant tumor regression in patients with metastatic melanoma, with objective response rates up to 52%. Studies have demonstrated that CD8+ TILs, which are part of this treatment, have strong antitumor effects and can mediate durable remission in certain cancers. ^{1 2 3 4 5}

Is adoptive cell therapy for melanoma safe for humans?

Adoptive cell therapy for melanoma, which involves using tumor-infiltrating lymphocytes (TIL) and interleukin-2 (IL-2), has shown significant response rates in patients but also comes with notable IL-2 associated toxicity. This means while the treatment can be effective, it may also cause side effects related to IL-2, which should be considered when evaluating its safety. ^{2 4 6 7 8}

How is the treatment DP CD8 TIL, DP CD8 TIL KD for melanoma different from other treatments?

This treatment is unique because it uses a patient's own immune cells, specifically CD8+ T cells with stem-cell-like properties, to target and attack melanoma tumors, potentially leading to long-lasting remission. Unlike traditional treatments, it involves expanding these tumor-specific cells outside the body and then infusing them back into the patient to enhance their immune response against cancer. ^{1 3 7 9 10}

Eligibility Criteria

Adults over 18 with advanced solid tumors that are metastatic or unresectable, and have progressed after standard therapy. They must have a tumor large enough for cell extraction and meet specific blood, liver, and kidney function criteria. Women of childbearing age must avoid pregnancy during the trial.

Inclusion Criteria

I have a tumor larger than 1 cm that can be surgically removed.

I am older than 18 years.

I am fully active or restricted in physically strenuous activity but can do light work.

Exclusion Criteria

I haven't had cancer treatment or been in a trial in the last 2 weeks and have recovered from any past treatments.

My brain metastases are treated, stable for 4 weeks, and I'm not on high-dose steroids.

Any condition including medical, emotional, psychiatric, or logistical that, in the opinion of the Investigator, would preclude the patient from adhering to the protocol or would increase the risk associated with study participation or study drug administration or interfere with the interpretation of safety results.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Lymphodepleting Chemotherapy

Participants receive cyclophosphamide and fludarabine to facilitate proliferation and persistence of adoptively transferred T cells

1 week

Adoptive Cell Transfer

Participants receive an intravenous infusion of 1-40 billion tumor infiltrating lymphocytes (TIL) selected for tumor reactivity

1 day

High-dose IL-2 Administration

High-dose IL-2 is administered to enhance T-cell proliferation, persistence, and cytotoxicity

6 days

Low-dose IL-2 Administration

Low-dose subcutaneous IL-2 is administered in dose-escalation cohorts for 1, 2, or 3 weeks if tolerated

1-3 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

12 weeks

Treatment Details

Interventions

• DP CD8 TIL
• DP CD8 TIL KD
• Low dose IL-2

Trial Overview The study tests adoptive cell therapy using autologous CD8+ TIL (tumor infiltrating lymphocytes) selected for their cancer-fighting potential in patients with various solid tumors. Patients will receive an infusion of these cells along with low-dose IL-2 to enhance treatment efficacy.

Participant Groups

Group I: DP CD8 TIL KD Experimental Treatment 2 Interventions

Adoptive Cell Transfer of tumor infiltrating lymphocytes that were selected for tumor reactivity by the expression of cell surface proteins CD39 and CD103 and expanded in vitro in the presence of PH-762, a silencing RNA that reduces the expression of the checkpoint inhibitor PD-1. A suspension of 1-40 billion cells will be delivered one time by intravenous infusion.

Group II: DP CD8 TIL Experimental Treatment 2 Interventions

Adoptive Cell Transfer of tumor infiltrating lymphocytes that were selected for tumor reactivity by the expression of cell surface proteins CD39 an CD103 and expanded in vitro. A suspension of 1-40 billion cells will be delivered one time by intravenous infusion.

DP CD8 TIL is already approved in United States for the following indications:

Approved in United States as Lifileucel (Amtagvi) for:

• Advanced melanoma that has worsened after treatment with certain immunotherapy drugs or targeted therapies

Who Is Running the Clinical Trial?

AgonOx, Inc.

Lead Sponsor

Trials

1

Recruited

20+

Phio Pharmaceuticals Inc.

Industry Sponsor

Trials

2

Recruited

50+

Phio Pharmaceuticals Corp.

Collaborator

Trials

1

Recruited

20+

Providence St Joseph Health

Collaborator

Trials

2

Recruited

40+

Findings from Research

Adoptive cell immunotherapy using expanded autologous tumor-infiltrating lymphocytes can lead to long-lasting remission in some cancers, particularly metastatic melanoma.

The study highlights that successful treatment requires the infusion of tumor-specific CD8+ T cells with stem-cell-like properties, which are crucial for achieving complete and durable control of the disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Not All Tumor-Infiltrating CD8+ T Cells Are Created Equal. Held, W., Speiser, DE.[2021]

Adoptive transfer of autologous tumor infiltrating lymphocytes (TILs) has shown a 50% objective clinical response rate in patients with advanced malignant melanoma, indicating significant efficacy in this treatment approach.

A new method for expanding TILs to clinically relevant quantities within 8 weeks has been established, allowing for the generation of TILs with specific activity against tumor cells and tumor-associated antigens when autologous tumor is available.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Characterization of ex vivo expanded tumor infiltrating lymphocytes from patients with malignant melanoma for clinical application. Junker, N., Thor Straten, P., Andersen, MH., et al.[2021]

In a study of 44 patients with metastatic melanoma, 20% had CD4+ tumor-infiltrating lymphocytes (TIL) that showed specific reactivity against their tumors, indicating that these cells may play a role in tumor recognition and regression.

A case study demonstrated that administering CD4+ TIL along with high-dose interleukin-2 therapy led to significant regression of metastatic disease in a patient, suggesting that CD4+ TIL could enhance the effectiveness of adoptive cell therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tumor-specific CD4+ melanoma tumor-infiltrating lymphocytes. Friedman, KM., Prieto, PA., Devillier, LE., et al.[2022]

Adoptive cell therapy using autologous tumor infiltrating lymphocytes (TIL) has shown promising results, with objective response rates of up to 52% in patients with advanced metastatic melanoma.

The treatment involves activating and expanding TILs outside the body before re-infusing them into the patient, followed by administration of Interleukin-2 (IL-2) to enhance the immune response.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Key Factors in Clinical Protocols for Adoptive Cell Therapy in Melanoma. Considine, B., Hurwitz, ME.[2023]

CD8-positive tumor-infiltrating lymphocytes (TIL) demonstrated a strong antitumor effect against autologous tumor cells in vitro, indicating their potential as effective effector cells in specific immunotherapy for cancer.

In a preliminary clinical study, patients treated with CD8-positive TIL showed significant antitumor activity without serious side effects, suggesting that TIL therapy could be a safer and promising option compared to other treatments like LAK therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Fundamental and clinical aspects of adoptive immunotherapy with tumor-infiltrating lymphocytes]. Yahata, G., Okada, Y., Honda, S., et al.[2008]

Adoptive cell therapy (ACT) using tumor-infiltrating lymphocytes (TIL) has shown high response rates (up to 72%) in metastatic melanoma, but selecting tumor-reactive TIL is challenging and limits treatment eligibility.

An optimized method for enriching CD8(+) cells from young TIL cultures was developed, which improved tumor recognition and expansion, suggesting it could enhance the effectiveness of ACT by combining the advantages of both selected and minimally cultured TIL.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Enrichment of CD8+ cells from melanoma tumor-infiltrating lymphocyte cultures reveals tumor reactivity for use in adoptive cell therapy. Prieto, PA., Durflinger, KH., Wunderlich, JR., et al.[2021]

The addition of an agonistic anti-4-1BB antibody during the culture of melanoma tumor fragments significantly enhances the growth of memory CD8(+) T cells that are specific to melanoma antigens, indicating a potential strategy to improve adoptive cell therapy outcomes.

This approach not only boosts the expansion of tumor-reactive T cells but also activates dendritic cells within the tumor fragments, suggesting that the tumor microenvironment can be manipulated to optimize T cell responses for cancer treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Manipulating the tumor microenvironment ex vivo for enhanced expansion of tumor-infiltrating lymphocytes for adoptive cell therapy. Chacon, JA., Sarnaik, AA., Chen, JQ., et al.[2021]

In a pilot study involving 6 patients with metastatic melanoma, the combination of tumor-infiltrating lymphocyte (TIL) therapy and low-dose IL-2 injections resulted in significant reductions in treatment-related toxicity, with no severe adverse events reported.

The treatment led to objective clinical responses in 2 patients, with ongoing complete responses lasting over 10 months, suggesting that low-dose IL-2 can enhance the safety and efficacy of adoptive cell therapy for melanoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adoptive cell therapy with autologous tumor infiltrating lymphocytes and low-dose Interleukin-2 in metastatic melanoma patients. Ellebaek, E., Iversen, TZ., Junker, N., et al.[2021]

Adoptive transfer of autologous tumor-infiltrating lymphocytes has shown objective cancer regression in 49-72% of patients with metastatic melanoma, highlighting its efficacy as a treatment option.

In a pilot trial combining cell transfer with lymphodepleting regimens, 40% of patients achieved complete and durable responses lasting beyond 3 to 7 years, demonstrating the potential for long-term remission.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cell transfer immunotherapy for metastatic solid cancer--what clinicians need to know. Rosenberg, SA.[2021]

In a phase II clinical trial involving 31 patients with metastatic melanoma, adoptive cell therapy using autologous tumor-infiltrating lymphocytes (TIL) resulted in a 48.4% objective clinical response rate, with 6.5% of patients achieving complete remission.

The study found that a higher number of infused TIL, particularly those with a greater proportion of CD8(+) T cells and a more differentiated effector phenotype, were significantly associated with better tumor regression outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Specific lymphocyte subsets predict response to adoptive cell therapy using expanded autologous tumor-infiltrating lymphocytes in metastatic melanoma patients. Radvanyi, LG., Bernatchez, C., Zhang, M., et al.[2022]

References

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

Not All Tumor-Infiltrating CD8+ T Cells Are Created Equal. [2021]

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

Characterization of ex vivo expanded tumor infiltrating lymphocytes from patients with malignant melanoma for clinical application. [2021]

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

Tumor-specific CD4+ melanoma tumor-infiltrating lymphocytes. [2022]

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

Key Factors in Clinical Protocols for Adoptive Cell Therapy in Melanoma. [2023]

5. Japan pubmed.ncbi.nlm.nih.gov

[Fundamental and clinical aspects of adoptive immunotherapy with tumor-infiltrating lymphocytes]. [2008]

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

Enrichment of CD8+ cells from melanoma tumor-infiltrating lymphocyte cultures reveals tumor reactivity for use in adoptive cell therapy. [2021]

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

Manipulating the tumor microenvironment ex vivo for enhanced expansion of tumor-infiltrating lymphocytes for adoptive cell therapy. [2021]

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

Adoptive cell therapy with autologous tumor infiltrating lymphocytes and low-dose Interleukin-2 in metastatic melanoma patients. [2021]

9. England pubmed.ncbi.nlm.nih.gov

Cell transfer immunotherapy for metastatic solid cancer--what clinicians need to know. [2021]

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

Specific lymphocyte subsets predict response to adoptive cell therapy using expanded autologous tumor-infiltrating lymphocytes in metastatic melanoma patients. [2022]