Adoptive Cell Therapy for Melanoma
(ACT Trial)
Recruiting in Palo Alto (17 mi)
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1
Recruiting
Sponsor: AgonOx, Inc.
Must not be taking: Corticosteroids, Immunosuppressives
Disqualifiers: Active brain metastases, Autoimmune disease, others
No Placebo Group
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.
12345Is 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.
24678How 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.
137910Eligibility 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.
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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.
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Trial 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
Participant Groups
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.
2Treatment groups
Experimental Treatment
Group I: DP CD8 TIL KDExperimental Treatment2 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 TILExperimental Treatment2 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
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Providence Portland Medical CenterPortland, OR
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Who Is Running the Clinical Trial?
AgonOx, Inc.Lead Sponsor
Phio Pharmaceuticals Inc.Industry Sponsor
Phio Pharmaceuticals Corp.Collaborator
Providence St Joseph HealthCollaborator
References
Not All Tumor-Infiltrating CD8+ T Cells Are Created Equal. [2021]Adoptive cell immunotherapy using in vitro expanded autologous tumor-infiltrating lymphocytes has the potential to mediate durable remission of certain types of cancer. A recent paper in Science shows that complete and durable control of metastatic melanoma requires the infusion of tumor-specific CD8+ T cells that have stem-cell-like properties.
Characterization of ex vivo expanded tumor infiltrating lymphocytes from patients with malignant melanoma for clinical application. [2021]Clinical trials of adoptive transfer of autologous tumor infiltrating lymphocytes (TILs) to patients with advanced malignant melanoma have shown remarkable results with objective clinical responses in 50% of the treated patients. In order to initiate a clinical trial in melanoma, we have established a method for expanding TILs to clinical relevant quantities in two steps with in 8 weeks. Further characterization of expanded TILs revealed an oligoclonal composition of T-cells with an effector memory like phenotype. When autologous tumor was available, TILs showed specific activity in all patients tested. TIL cultures contained specificity towards tumor cells as well as peptides derived from tumor-associated antigens (TAAs) during expansion procedures.
Tumor-specific CD4+ melanoma tumor-infiltrating lymphocytes. [2022]Adoptive cell therapy using tumor-infiltrating lymphocytes (TIL) can mediate objective and durable tumor regressions in patients with metastatic melanoma. CD8+ tumor-reactive TIL are well studied in humans and animals, yet the function of tumor-infiltrating CD4+ T lymphocytes in patient treatments remains controversial. We recently demonstrated that CD4+ TILs are not necessary for objective responses in patients. Coinfusion with tumor-specific CD4 TIL may enhance or increase the durability of tumor regressions, but the number of patients with tumor-reactive CD4 TIL is unknown. We screened 44 CD8+-depleted TIL for in vitro reactivity against autologous tumor. Nine (20%) showed specific reactivity by interferon-γ release assay, of which 8 were specifically blocked by an anti-HLA-DR antibody. Flow-cytometric analysis of these reactive TIL confirmed a high CD4+ composition (median 89%). Highlighting the contribution of CD4+ TIL to tumor regression, a patient with widespread metastatic disease was administered TIL containing HLA class II-restricted tumor activity with high-dose interleukin-2 therapy after lymphodepletion that mediated regression of extensive metastatic disease in the liver and spleen. These results demonstrate that at least 20% of metastatic melanomas contain CD4+ lymphocytes with specific tumor recognition and suggest a possible role for CD4+ cells in the effectiveness of adoptive cell therapy.
Key Factors in Clinical Protocols for Adoptive Cell Therapy in Melanoma. [2023]Adoptive cell therapy (ACT) with autologous tumor infiltrating lymphocytes (TIL) has been studied for patients with advanced metastatic cancers (primarily melanoma) for decades and has changed significantly during that period. Treatment with TIL includes ex vivo cell activation and expansion followed by re-infusion of these cells into the patient. After cell infusion, patients receive Interleukin-2 (IL-2). Objective response rates up to 52% have been seen in patients with metastatic melanoma. Efforts to improve TIL therapy include better selection and expansion of tumor-reactive lymphocytes, optimization of IL-2 or other T cell activating cytokine dosing, and, potentially, genetic manipulation of the immune cell product. Here we describe methods involved in the collection, expansion, and treatment with TIL for patients with metastatic melanoma.
[Fundamental and clinical aspects of adoptive immunotherapy with tumor-infiltrating lymphocytes]. [2008]Fundamental analysis was conducted on the phenotype and function of autologous tumor-infiltrating lymphocytes (TIL) in terms of their role as effector cells in specific immunotherapy for malignant tumors. Their effects were further examined in a preliminary clinical study. Analysis of the phenotype of lymphocytes which infiltrate tumor tissue and proliferate in the presence of IL-2, by using cell-surface subset markers, revealed proliferation of two types of lymphocytes: CD8-positive cytotoxic/suppressor T-cells and CD4-positive helper/suppressor inducer T-cells. In vitro cytotoxicity tests on these lymphocytes for antitumor activity showed that only CD8-positive lymphocytes had a much stronger antitumor effect on autologous tumor cells than LAK cells. In contrast, they showed no antitumor effect on autologous normal cells or homologous tumor cells of the same histological type, indicating specificity of their antitumor activity. Furthermore, in vitro treatment of tumor cells with interferon was found to increase both expression of MHC class I antigens and sensitivity to TIL cytotoxicity. In vitro of the close relationship between induction of CD8-positive TIL and expression of HLA (A, B, C) antigens in tumor tissue, the above findings suggest that the presence or absence of expression of MHC class I antigens plays an important role in the efficacy of adoptive immunotherapy with TIL. Significant antitumor activity was observed in patients given CD8-positive cells in a preliminary clinical study, the same as in in vitro assay. No patient showed serious side effects such as the pulmonary edema or body fluid retention observed in LAK therapy. Specific immunotherapy using TIL seems to be a promising modality in multidisciplinary treatment of cancer. Further developments from research on this subject are expected.
Enrichment of CD8+ cells from melanoma tumor-infiltrating lymphocyte cultures reveals tumor reactivity for use in adoptive cell therapy. [2021]Adoptive cell therapy (ACT) using tumor-infiltrating lymphocytes (TIL) for metastatic melanoma has shown objective response rates as high as 72%. The successful application of this therapy requires the selection of unique tumor-reactive lymphocyte cultures for each patient. This is a technically and logistically difficult undertaking, and patients who do not have tumor-reactive TIL are not considered eligible for treatment. To simplify the methods of TIL generation and extend TIL-based immunotherapy to additional patients, methods were developed to use unselected, minimally cultured ("young") TIL. Young TIL cultures contain a variable number of CD8(+), CD4(+), and CD3(-)CD56(+) natural killer cells. In this study we retrospectively investigated a role for these subsets in the clinical outcome of patients treated with TIL derived from selected microcultures. This analysis demonstrated a suggestive but nonsignificant association between the number of CD8(+) cells administered and tumor regression. We therefore investigated the feasibility of selecting CD8(+) cells from young TIL cultures for ACT therapy. The available methods for clinical scale CD8(+) enrichment proved inadequate for TIL, so an optimized CD8(+) enrichment method was developed and is reported here. We observed that CD8 (+)enrichment of some TIL cultures revealed in vitro tumor recognition that was not evident in bulk culture, and an improved in vitro recognition of tumor in other TIL cultures. In addition, the enriched CD8(+) young TIL expanded more reliably and predictably in rapid expansions than the bulk TIL. Thus, optimized CD8(+) selection combines the benefits of antigen-selected TIL and young TIL for generating lymphocyte cultures for ACT, and should be evaluated in cell transfer therapy protocols.
Manipulating the tumor microenvironment ex vivo for enhanced expansion of tumor-infiltrating lymphocytes for adoptive cell therapy. [2021]Cultured tumor fragments from melanoma metastases have been used for years as a source of tumor-infiltrating lymphocytes (TIL) for adoptive cell therapy (ACT). The expansion of tumor-reactive CD8(+) T cells with interleukin-2 (IL2) in these early cultures is critical in generating clinically active TIL infusion products, with a population of activated 4-1BB CD8(+) T cells recently found to constitute the majority of tumor-specific T cells.
Adoptive cell therapy with autologous tumor infiltrating lymphocytes and low-dose Interleukin-2 in metastatic melanoma patients. [2021]Adoptive cell therapy may be based on isolation of tumor-specific T cells, e.g. autologous tumor infiltrating lymphocytes (TIL), in vitro activation and expansion and the reinfusion of these cells into patients upon chemotherapy induced lymphodepletion. Together with high-dose interleukin (IL)-2 this treatment has been given to patients with advanced malignant melanoma and impressive response rates but also significant IL-2 associated toxicity have been observed. Here we present data from a feasibility study at a Danish Translational Research Center using TIL adoptive transfer in combination with low-dose subcutaneous IL-2 injections.
Cell transfer immunotherapy for metastatic solid cancer--what clinicians need to know. [2021]Cancer immunotherapy using the adoptive transfer of autologous tumor-infiltrating lymphocytes results in objective cancer regression in 49-72% of patients with metastatic melanoma. In a pilot trial combining cell transfer with a maximum lymphodepleting regimen, complete durable responses were seen in 40% of patients, with complete responses ongoing beyond 3 to 7 years. Current approaches to cell transfer therapy using autologous cells genetically engineered to express conventional or chimeric T-cell receptors have mediated cancer regression in patients with metastatic melanoma, synovial sarcoma, neuroblastoma and refractory lymphoma. Adoptive cell transfer immunotherapy is a rapidly developing new approach to the therapy of metastatic cancer in humans. This Review will emphasize the current available applications of cell transfer immunotherapy for patients with cancer.
Specific lymphocyte subsets predict response to adoptive cell therapy using expanded autologous tumor-infiltrating lymphocytes in metastatic melanoma patients. [2022]Adoptive cell therapy (ACT) using autologous tumor-infiltrating lymphocytes (TIL) is a promising treatment for metastatic melanoma unresponsive to conventional therapies. We report here on the results of an ongoing phase II clinical trial testing the efficacy of ACT using TIL in patients with metastatic melanoma and the association of specific patient clinical characteristics and the phenotypic attributes of the infused TIL with clinical response.