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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new treatment for individuals with advanced solid tumors, such as melanoma, that have spread or cannot be surgically removed. The treatment uses a special type of immune cells called tumor-infiltrating lymphocytes (TIL), which are enhanced in the lab to better combat cancer. Participants will receive these enhanced cells through an IV infusion. The trial seeks individuals whose cancer has worsened despite standard treatments and who have a tumor suitable for creating the TIL therapy. 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 therapy.

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.

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

Research has shown that adoptive cell therapy, which uses tumor-infiltrating lymphocytes (TIL), has potential in treating various cancers, including melanoma. Studies have found significant improvements, particularly in advanced melanoma. Most patients tolerate TIL therapy well, though it can cause some side effects. These side effects are usually manageable and may include flu-like symptoms or fatigue.

For the DP CD8 TIL KD treatment, less safety information is available, but early research suggests that adding silencing RNA to lower PD-1 levels might enhance results. PD-1 is a protein that can prevent the immune system from attacking cancer cells. This method remains under investigation, but initial treatments have been generally safe, with side effects similar to those of standard TIL therapy.

As this is a phase 1 trial, the main goal is to ensure the treatment's safety. Phase 1 trials typically focus on finding the right dose and monitoring for any side effects. Reactions are closely monitored to ensure participant safety. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about DP CD8 TIL and DP CD8 TIL KD because they represent a novel approach to treating melanoma. Unlike traditional therapies like immune checkpoint inhibitors or targeted therapies, these treatments involve adoptive cell transfer using tumor-infiltrating lymphocytes (TILs) selected for their tumor-fighting abilities. The DP CD8 TIL KD arm is particularly innovative, as it includes a silencing RNA called PH-762 to reduce PD-1 expression, potentially enhancing the TILs' ability to attack cancer cells. These treatments could offer a more personalized and potentially more effective option by directly harnessing the body's immune system to fight melanoma.

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

Research has shown that adoptive cell therapy, which uses special immune cells from tumors, holds promise for treating melanoma, a type of skin cancer. Studies have found that this treatment can shrink tumors in 36% to 56% of patients. In some cases, the cancer becomes undetectable, known as complete remission. In this trial, participants may receive the DP CD8 TIL treatment, which involves adoptive cell transfer of tumor-infiltrating lymphocytes. Another arm of the trial involves the DP CD8 TIL KD treatment, which enhances this approach by using a special RNA to lower levels of PD-1, a protein that can weaken the immune system's fight against cancer. This method aims to make immune cells more effective at attacking cancer, offering hope for better results in difficult-to-treat cases. ^{6 7 8 9 10}

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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 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 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]

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 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]

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 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]

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 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]

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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9455018/

Tumor Infiltrating Lymphocyte (TIL) Therapy for Solid ... More recently, the observed objective clinical response rate in patients with advanced melanoma was 50%, including two complete response and three partial ...

2. sciencedirect.com sciencedirect.com/science/article/pii/S2666636724007838

Tumor-Infiltrating Lymphocyte Therapy: A New Frontier Originally considered a niche treatment that would have efficacy only against melanoma, TIL therapy is now demonstrating promising activity in a growing number ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC3315690/

Adoptive T-cell Therapy Using Autologous Tumor-infiltrating ... Metastatic melanoma patients were initially treated with TIL and IL-2 without lymphodepletion, resulting in a response rate of 39% (8, 63–65). However, a series ...

4. aacrjournals.org aacrjournals.org/clincancerres/article/31/13/2628/763094/Effective-TIL-Therapy-for-Patients-with-Checkpoint

Effective TIL Therapy for Patients with Checkpoint-Resistant ... Although 43% of the treatment-naïve patients obtained clinical benefit, this was only 20% of the patients that relapsed after ICB therapy. The majority of ...

5. link.springer.com link.springer.com/article/10.1007/s00262-024-03793-4

Recent clinical researches and technological development ... Melanoma has been studied in TIL therapy for 30 years and represents a highly immunogenic indication, with objective response rate (ORR) 36%-56% ...

6. astctjournal.org astctjournal.org/article/S2666-6367(24)00783-8/fulltext

Tumor-Infiltrating Lymphocyte Therapy: A New Frontier This trial indicated that TIL therapy could achieve durable and meaningful responses in NSCLC, including in the important subset of never-smoker lung cancer ...

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11393248/

Recent clinical researches and technological development in ... TIL therapy is investigated for a wide range of solid tumors, including melanoma, cervical cancer, lung cancer, breast cancer, and more recently ...

8. nature.com nature.com/articles/s41591-024-03418-4

Personalized, autologous neoantigen-specific T cell ... Thus far, most ACT successes for advanced melanoma have been observed with TIL treatment: favorable phase 2 and 3 clinical trial results have ...

9. sciencedirect.com sciencedirect.com/science/article/pii/S2666636724003683

Defining the Quality Attributes for Tumor-Infiltrating ... This section will describe the TIL DP attributes associated with clinical efficacy or safety, considered QAs of TIL MPs, in conventional pharmaceutical ...

10. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC3514199/

Adoptive cell therapy with autologous tumor infiltrating ... Results from this trial, including safety data, clinical and immunological outcome are reported in the following. Materials and methods. Patients. Patients ...