Adoptive T Cell Therapy for Melanoma
Recruiting in Palo Alto (17 mi)
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1
Recruiting
Sponsor: Loyola University
Must not be taking: Steroids, Antibiotics
Disqualifiers: Pregnancy, Brain metastases, Severe disease, others
No Placebo Group
Trial Summary
What is the purpose of this trial?Phase I clinical trial to determine the Phase II dose of autologous TIL 1383I TCR gene modified T Cells using a retrovirus. This is a novel National Cancer Institute (NCI) funded investigator initiated therapy for patients with advanced melanoma.
Will I have to stop taking my current medications?
The trial does not specify if you need to stop taking your current medications, but it does mention that patients taking steroids for disease control or pain management are excluded. It also requires a waiting period after certain treatments, like a 6-week gap after anti-CTLA-4 treatment and a 4-week gap after anti-PD-1 or anti-PD-L1 treatment.
What data supports the effectiveness of the treatment Autologous TIL 1383I TCR Gene Modified T Cells for melanoma?
Research shows that adoptive cell therapy using tumor-infiltrating lymphocytes (TILs) has led to significant responses in about 50% of patients with metastatic melanoma. Additionally, T cells modified with specific T-cell receptors (TCRs) have shown promise in targeting melanoma cells, suggesting potential effectiveness of this treatment.
12345Is adoptive T cell therapy for melanoma safe?
Initial studies show that genetically engineered T cells can cause tumor regression, but there are safety concerns like 'on-target, off-organ' toxicity, which means the treatment might affect healthy tissues. Efforts are being made to improve safety by carefully selecting target antigens and enhancing T cell receptor design.
15678What makes the treatment Autologous TIL 1383I TCR Gene Modified T Cells unique for melanoma?
This treatment is unique because it involves modifying a patient's own T cells to specifically target melanoma cells by introducing a gene for a T-cell receptor (TCR) that recognizes a melanoma-associated antigen. This approach aims to enhance the body's immune response against the cancer, offering a personalized and potentially more effective treatment option compared to traditional therapies.
135910Eligibility Criteria
Adults with advanced melanoma that can be measured, who are in good physical condition (ECOG PS of 0 or 1), and have tried certain treatments without success. They must not be pregnant, vulnerable individuals, or have severe infections or other health conditions that could interfere with the trial.Inclusion Criteria
My melanoma has spread and can be measured by tests or seen on scans.
Patients must consent to be in the study and must have signed and dated an approved consent form, which conforms to federal and institutional guidelines.
My heart and lungs are strong enough for IL-2 treatment.
+9 more
Exclusion Criteria
I have not had active brain melanoma or treatment for it in the last 3 months.
Your blood test results show low levels of white blood cells or platelets, or high levels of certain liver or kidney markers.
Special classes of subjects such as fetuses, pregnant women, children, prisoners, institutionalized individuals, or others who are likely to be vulnerable.
+13 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Treatment
Participants receive escalating doses of TIL 1383I TCR transduced T cells to determine the maximum tolerated dose
4 weeks
3 visits (in-person) for each cohort
Follow-up
Participants are monitored clinically and immunologically for safety and effectiveness after T cell infusion
1 year
Regular visits (in-person) over the year
Participant Groups
This Phase I trial is testing escalating doses of genetically modified T cells to treat advanced melanoma. It's funded by the NCI and aims to find the right dose for Phase II trials. Participants receive a retrovirus-modified version of their own T cells.
1Treatment groups
Experimental Treatment
Group I: Escalating DosesExperimental Treatment1 Intervention
Three patients will be treated at the first \& each subsequent dose level. Patients will be observed for 30 days post T cell infusion. If there was one DLT in the first 3 patients, an additional 3 patients will be treated at that level. If no additional DLTs are observed (for a total of 1 DLT in 6 patients) then the dose will be escalated. If two patients in the first 3 patients at a dose level experience a DLT, the dose will be de-escalated to the previous level \& an additional 3 patients will be enrolled at that level if 6 have not yet been treated at that level. The maximum tolerated dose (MTD) is defined as the highest dose at which 0 or 1 patient in six has experienced a DLT. If 2 or 3 patients in the first 3 patients experience a DLT at the first dose level, the study will terminate.
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Loyola University Medical CenterMaywood, IL
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Who Is Running the Clinical Trial?
Loyola UniversityLead Sponsor
National Cancer Institute (NCI)Collaborator
References
[Application of gene therapy in tumor adoptive immunotherapy]. [2012]Adoptive cell transfer of tumor-infiltrating lymphocyte (TIL) has resulted in clear and reproducible responses in a substantial percentage (approximately 50%) of patients with metastatic melanoma. The availability of tumor reactive TIL limits the use of adoptive cell transfer for the treatment of most non-melanoma cancer patients. Recent report indicated that adoptive transfer of T lymphocytes genetically modified with T-cell receptor (TCR) against a tumor antigen resulted in objective response in melanoma patients, thus shedding light on the use of this strategy for the treatment of common epithelial cancers beyond melanoma. In this review, the current status and potential use of genetic modification in the adoptive immunotherapy of cancer patients are be discussed.
Simultaneous generation of CD8+ and CD4+ melanoma-reactive T cells by retroviral-mediated transfer of a single T-cell receptor. [2007]Adoptive immunotherapy of cancer requires the generation of large numbers of tumor antigen-reactive T cells for transfer into cancer patients. Genes encoding tumor antigen-specific T-cell receptors can be introduced into primary human T cells by retroviral mediated gene transfer as a potential method of providing any patient with a source of autologous tumor-reactive T cells. A T-cell receptor-specific for a class I MHC (HLA-A2)-restricted epitope of the melanoma antigen tyrosinase was isolated from a CD4(+) tumor-infiltrating lymphocyte (TIL 1383I) and introduced into normal human peripheral blood lymphocytes by retroviral transduction. T-cell receptor-transduced T cells secreted various cytokines when cocultured with tyrosinase peptide-loaded antigen-presenting cells as well as melanoma cells in an HLA-A2-restricted manner, and could also lyse target cells. Furthermore, T-cell clones isolated from these cultures showed both CD8(+) and CD4(+) transduced T cells could recognize HLA-A2(+) melanoma cells, giving us the possibility of engineering class I MHC-restricted effector and T helper cells against melanoma. The ability to confer class I MHC-restricted tumor cell recognition to CD4(+) T cells makes the TIL 1383I TCR an attractive candidate for T-cell receptor gene transfer-based immunotherapy.
Adoptive immunotherapy of disseminated leukemia with TCR-transduced, CD8+ T cells expressing a known endogenous TCR. [2021]Adoptive T-cell immunotherapy has shown promise in the treatment of human malignancies, but the challenge of isolating T cells with high avidity for tumor antigens in each patient has limited application of this approach. The transfer into T cells of T-cell receptor (TCR) genes encoding high-affinity TCRs recognizing defined tumor-associated antigens can potentially circumvent this obstacle. Using a well-characterized murine model of adoptive T-cell immunotherapy for widely disseminated leukemia, we demonstrate that TCR gene-modified T cells can cure mice of disseminated tumor. One goal of such adoptive therapy is to establish a persistent memory response to prevent recurrence; however, long-term function of transferred TCR-transduced T cells is limited due to reduced expression of the introduced TCR in vivo in quiescent resting T cells. However, by introducing the TCR into a cell with a known endogenous specificity, activation of these T cells by stimulation through the endogenous TCR can be used to increase expression of the introduced TCR, potentially providing a strategy to increase the total number of tumor-reactive T cells in the host and restore more potent antitumor activity.
Adoptive Cell Therapy for Metastatic Melanoma. [2018]Adoptive cell therapy (ACT) of tumor-infiltrating lymphocytes (TILs) is a powerful form of immunotherapy by inducing durable complete responses that significantly extend the survival of melanoma patients. Mutation-derived neoantigens were recently identified as key factors for tumor recognition and rejection by TILs. The isolation of T-cell receptor (TCR) genes directed against neoantigens and their retransduction into peripheral T cells may provide a new form of ACT.Genetic modifications of T cells with chimeric antigen receptors (CARs) have demonstrated remarkable clinical results in hematologic malignancies, but are so far less effective in solid tumors. Only very limited reports exist in melanoma. Progress in CAR T-cell engineering, including neutralization of inhibitory signals or additional safety switches, may open opportunities also in melanoma.We review clinical results and latest developments of adoptive therapies with TILs, T-cell receptor, and CAR-modified T cells and discuss future directions for the treatment of melanoma.
MART-1 TCR gene-modified peripheral blood T cells for the treatment of metastatic melanoma: a phase I/IIa clinical trial. [2022]Adoptive cell therapy with peripheral blood T cells expressing transgenic T-cell receptors (TCRs) is an innovative therapeutic approach for solid malignancies. We investigated the safety and feasibility of adoptive transfer of autologous T cells expressing melanoma antigen recognized by T cells 1 (MART-1)-specific TCR, cultured to have less differentiated phenotypes, in patients with metastatic melanoma.
Improving the efficacy and safety of engineered T cell therapy for cancer. [2020]Adoptive T-cell therapy (ACT) using tumor-infiltrating lymphocytes (TILs) is a powerful immunotherapeutics approach against metastatic melanoma. The success of TIL therapy has led to novel strategies for redirecting normal T cells to recognize tumor-associated antigens (TAAs) by genetically engineering tumor antigen-specific T cell receptors (TCRs) or chimeric antigen receptor (CAR) genes. In this manner, large numbers of antigen-specific T cells can be rapidly generated compared with the longer term expansion of TILs. Great efforts have been made to improve these approaches. Initial clinical studies have demonstrated that genetically engineered T cells can mediate tumor regression in vivo. In this review, we discuss the development of TCR and CAR gene-engineered T cells and the safety concerns surrounding the use of these T cells in patients. We highlight the importance of judicious selection of TAAs for modified T cell therapy and propose solutions for potential "on-target, off-organ" toxicity.
Genetic Modification of Tumor-Infiltrating Lymphocytes via Retroviral Transduction. [2021]Adoptive T cell therapy (ACT) holds great promise for cancer treatment. One approach, which has regained wide interest in recent years, employs antitumor T cells isolated from tumor lesions ("tumor-infiltrating lymphocytes" or TIL). It is now appreciated that a considerable proportion of anti-melanoma TIL recognize new HLA-binding peptides resulting from somatic mutations, which occurred during tumor progression. The clinical efficacy of TIL can potentially be improved via their genetic modification, designed to enhance their survival, homing capacity, resistance to suppression, tumor killing ability and additional properties of clinical relevance. Successful implementation of such gene-based strategies critically depends on efficient and reproducible protocols for gene delivery into clinical TIL preparations. Here we describe an optimized protocol for the retroviral transduction of TIL. As the experimental system we employed anti-melanoma TIL cultures prepared from four patients, recombinant retrovirus encoding an anti-CD19 chimeric antigen receptor (CAR) as a model gene of interest and CD19+ and CD19- human cell lines serving as target cells. Transduction on day 7 of the rapid expansion protocol (REP) resulted in 69 ± 8% CAR positive TIL. Transduced, but not untransduced TIL, from the four patients responded robustly to CD19+, but not CD19- cell lines, as judged by substantial secretion of IFN-γ following co-culture. In light of the rekindled interest in antitumor TIL, this protocol can be incorporated into a broad range of gene-based approaches for improving the in-vivo survival and functionality of TIL in the clinical setting.
Selecting highly affine and well-expressed TCRs for gene therapy of melanoma. [2021]A recent phase 1 trial has demonstrated that the generation of tumor-reactive T lymphocytes by transfer of specific T-cell receptor (TCR) genes into autologous lymphocytes is feasible. However, compared with results obtained by infusion of tumor-infiltrating lymphocytes, the response rate observed in this first TCR gene therapy trial is low. One strategy that is likely to enhance the success rate of TCR gene therapy is the use of tumor-reactive TCRs with a higher capacity for tumor cell recognition. We therefore sought to develop standardized procedures for the selection of well-expressed, high-affinity, and safe human TCRs. Here we show that TCR surface expression can be improved by modification of TCR alpha and beta sequences and that such improvement has a marked effect on the in vivo function of TCR gene-modified T cells. From a panel of human, melanoma-reactive TCRs we subsequently selected the TCR with the highest affinity. Furthermore, a generally applicable assay was used to assess the lack of alloreactivity of this TCR against a large series of common human leukocyte antigen alleles. The procedures described in this study should be of general value for the selection of well- and stably expressed, high-affinity, and safe human TCRs for subsequent clinical testing.
Monoclonal T-cell receptors: new reagents for cancer therapy. [2022]Adoptive transfer of antigen-specific T lymphocytes is an effective form of immunotherapy for persistent virus infections and cancer. A major limitation of adoptive therapy is the inability to isolate antigen-specific T lymphocytes reproducibly. The demonstration that cloned T-cell receptor (TCR) genes can be used to produce T lymphocyte populations of desired specificity offers new opportunities for antigen-specific T-cell therapy. TCR gene-modified lymphocytes display antigen-specific function in vitro, and were shown to protect against virus infection and tumor growth in animal models. A recent trial in humans demonstrated that TCR gene-modified T cells persisted in all and reduced melanoma burden in 2/15 patients. In future trials, it may be possible to use TCR gene transfer to equip helper and cytotoxic T cells with new antigen-specificity, allowing both T-cell subsets to cooperate in achieving improved clinical responses. Sequence modifications of TCR genes are being explored to enhance TCR surface expression, while minimizing the risk of pairing between introduced and endogenous TCR chains. Current T-cell transduction protocols that trigger T-cell differentiation need to be modified to generate "undifferentiated" T cells, which, upon adoptive transfer, display improved in vivo expansion and survival. Both, expression of only the introduced TCR chains and the production of naïve T cells may be possible in the future by TCR gene transfer into stem cells.
Exploiting the curative potential of adoptive T-cell therapy for cancer. [2023]Adoptive T-cell therapy (ACT) is a potent and flexible cancer treatment modality that can induce complete, durable regression of certain human malignancies. Long-term follow-up of patients receiving tumor-infiltrating lymphocytes (TILs) for metastatic melanoma reveals a substantial subset that experienced complete, lasting tumor regression - and may be cured. Increasing evidence points to mutated gene products as the primary immunological targets of TILs from melanomas. Recent technological advances permit rapid identification of the neoepitopes resulting from these somatic gene mutations and of T cells with reactivity against these targets. Isolation and adoptive transfer of these T cells may improve TIL therapy for melanoma and permit its broader application to non-melanoma tumors. Extension of ACT to other malignancies may also be possible through antigen receptor gene engineering. Tumor regression has been observed following transfer of T cells engineered to express chimeric antigen receptors against CD19 in B-cell malignancies or a T-cell receptor against NY-ESO-1 in synovial cell sarcoma and melanoma. Herein, we review recent clinical trials of TILs and antigen receptor gene therapy for advanced cancers. We discuss lessons from this experience and consider how they might be applied to realize the full curative potential of ACT.