Adoptive T-Cell Therapy Using Autologous Tumor-Infiltrating Lymphocytes for Metastatic Melanoma

Abstract

Immunotherapy using autologous T-cells has emerged to be a powerful treatment option for patients with metastatic melanoma. These include the adoptive transfer of autologous tumor-infiltrating lymphocytes (TIL), T-cells transduced with high-affinity T-cell receptors (TCR) against major melanosomal tumor antigens, and T cells transduced with chimeric antigen receptors (CAR) composed of hybrid immunoglobulin light chains with endo-domains of T-cell signaling molecules. Among these and other options for T-cell therapy, TIL together with high-dose IL-2 has had the longest clinical history with multiple clinical trials in centers across the world consistently demonstrating durable clinical response rates near 50% or more. A distinct advantage of TIL therapy making it still the T-cell therapy of choice is the broad nature of the T-cell recognition against both defined as well as un-defined tumors antigens against all possible MHC, rather than the single specificity and limited MHC coverage of the newer TCR and CAR transduction technologies. In the past decade, significant inroads have been made in defining the phenotypes of T cells in TIL mediating tumor regression. CD8+ T cells are emerging to be critical, although the exact subset of CD8+ T cells exhibiting the highest clinical activity in terms of memory and effector markers is still controversial. We present a model in which both effector-memory and more differentiated effector T cells ultimately may need to cooperate to mediate long-term tumor control in responding patients. Although TIL therapy has shown great potential to treat metastatic melanoma, a number of issues have emerged that need to be addressed to bring it more into the mainstream of melanoma care. First, we have a reached the point where a pivotal phase II or phase III trials are needed in an attempt to gain regulatory approval of TIL as standard-of-care. Second, improvements in how we expand TIL for therapy are needed, that minimize the time the T-cells are in culture and improve the memory and effector characteristics of the T cells for longer persistence and enhanced anti-tumor activity in vivo. Third, there is a critical need to identify surrogate and predictive biomarkers in order to better select suitable patients for TIL therapy in order to improve response rate and duration. Overall, the outlook for TIL therapy for melanoma is very bright. We predict that TIL will indeed emerge to become an approved treatment in the upcoming years through pivotal clinical trials. Moreover, new approaches combining TIL with targeted signaling pathway drugs, such as mutant B-RAF inhibitors, and synergistic immunomodulatory interventions enhancing T-cell costimulation and preventing negative regulation, should further increase therapeutic efficacy and durable complete response rates.

The mitochondrial dynamics in cancer and immune-surveillance

“…Infiltrating CTLs are known as tumor infiltrating lymphocytes (TILs) and have been associated with better survival outcome in various melanomas and carcinomas [194,195]. Interestingly, TILs are becoming an interesting target for adoptive cell immunotherapy (ACI) [196].…”

Extending the lifespan and efficacies of immune cells used in adoptive transfer for cancer immunotherapies–A review

“…Also CD4 C T cells can be given the ability to lyse tumor cells in an MHC class II independent manner when transfected with a CAR complex 60 Gamma delta cells have also been transduced with CARs directed to CD19 to allow significant expansion in response to CD19 thus removing the limitation that only one gamma delta subset is currently expandable (with aminobisphosphonates such as zolendrenic acid.). 61 The best clinical outcomes have so far come from autologous TILs with partial or complete clinical response rates (CRRs) of over 50% in melanoma 56 and more recently, using CARs with a CD19 directed antibody region to treat B cell leukaemias, where CRRs over 80% have been observed. 62 On the basis of these outcomes -a CAR therapy, CTL0019 -a CAR with CD19 joined to intracellular regions of CD3 z and 41BB has been granted FDA approval as a breakthrough therapy.…”

Current Status of Engineered T-Cell Therapy for Synovial Sarcoma

“…Initial approaches involved extraction of tumor-infiltrating lymphocytes (TILs) from tumor specimens, which were then expanded and re-infused in cancer patients [16,25]. The development of autologous T cells genetically engineered with a T-cell receptor (TCR) that recognizes tumor antigens has further improved the scalability and feasibility of ACT [26].…”