T Cell Receptor Gene Therapy for Cancer

Abstract

T cell-based adoptive immunotherapy has been shown to be a promising treatment for various types of cancer. However, adoptive T cell therapy currently requires the custom isolation and characterization of tumor-specific T cells from each patient-a process that can be not only difficult and time-consuming but also often fails to yield high-avidity T cells, which together have limited the broad application of this approach as a clinical treatment. Employing T cell receptor (TCR) gene therapy as a component of adoptive T cell therapy strategies can overcome many of these obstacles, allowing autologous T cells with a defined specificity to be generated in a much shorter time period. Initial studies using this approach have been hampered by a number of technical difficulties resulting in low TCR expression and acquisition of potentially problematic specificities due to mispairing of introduced TCR chains with endogenous TCR chains. The last several years have seen substantial progress in our understanding of the multiple facets of TCR gene therapy that will have to be properly orchestrated for this strategy to succeed. Here we outline the challenges of TCR gene therapy and the advances that have been made toward realizing the promise of this approach.

IL-15 enhances the antitumor effect of human antigen-specific CD8+T cells by cellular senescence delay

“…4,5 , 35 Recent studies of adoptive transfer with autologous T cells generated from patients have focused on generation of genetically modified memory CD8 C T cells with chimeric antigen receptors or T-cell receptors with a particular focus on improving the proliferation and persistence of T cells after transfer. [36][37][38][39][40] Traditionally, IL-2 has been a central component of T-cell expansion protocols. [41][42][43] However, IL-2-expanded T cells have significant limitations in adoptive therapy, including susceptibility to T-cell activation-induced cell death (AICD), Treg proliferation, and T-cell differentiation.…”

Chimeric antigen receptor modified T cell therapy for B cell malignancies

“…To circumvent the lack of high-avidity tumor reactive T cells, high-affinity tumorspecific receptors can be introduced by genetic modification into T cells that comprise the native repertoire and were not subject to central tolerance. Redirection of T cell specificity to a tumor can be accomplished by introduction of transgenes encoding a and b chains that encode a TCR specific for a tumor antigen or by introduction of tumor antigen-specific chimeric antigen receptors (CARs) [10,11]. These strategies endow modified T cells with the capacity to be activated through the introduced antigen receptor or their endogenously expressed TCR; hence their designation in some studies as bi-specific T cells.…”

Bad to the bone

“…1 E ver since descriptions of the various functional components of the hematopoietic stem cell niche, leukemia researchers have wondered whether leukemia stem cells (LSCs) require similar cell-extrinsic support for longterm maintenance of leukemia. 2 LSCs differ from normal hematopoietic stem cells (HSCs) in that they have activation of key pathways regulating self-renewal, proliferation, and survival.…”

“…1 Using a retroviral bone marrow transplantation model of blast-crisis chronic myeloid leukemia, the authors observed that mice with leukemia had a reduction in bone trabeculae and thinning of cortical bone compared with wild-type, nonleukemic controls. These bony changes were mediated through both reduced bone formation and increased osteoclastic bone resorption, and were partially reversible by treatment with bisphosphonate therapy (to inhibit osteoclast function).…”

“…1 A FIX protein designated FIX-ITV that contained 3 mutations (V181I, K265T, and I383V; see figure based on the wild-type FIX structure 6 ). FIX-ITV was demonstrated to promote coagulation in vitro in an aPTT assay when present at wild-type FIX levels in the absence of FVIII at ϳ 16% of the activity found when normal levels of wild-type FIX were present with normal levels of wild-type FVIII.…”