Molecular Pathways: Comparing the Effects of Drugs and T Cells to Effectively Target Oncogenes

Abstract

Mutant cancer-driving oncogenes are the best therapeutic targets, both with drugs like small-molecule inhibitors (SMI) and adoptive T-cell therapy (ATT), the most effective form of immunotherapy. Cancer cell survival often depends on oncogenes, which implies that they are homogenously expressed by all cancer cells and are difficult to select against. Mutant oncogene-directed therapy is relatively selective, as it targets preferentially the oncogene-expressing cancer cells. Both SMI and ATT can be highly effective in relevant preclinical models as well as selected clinical situations, and both share the risk of therapy resistance, facilitated by the frequent genetic instability of cancer cells. Recently, both therapies were compared in the same experimental model targeting the same oncogene. It showed that the oncogene-inactivating drug selected resistant clones, leading eventually to tumor relapse, whereas ATT eradicated large established tumors completely. The mode of tumor destruction likely explained the different outcome with only ATT destroying the tumor vasculature. Elucidating the cellular and molecular mechanisms responsible for tumor regression and relapse will define optimal conditions for the clinic. We argue that the ideal conditions of ATT in the experimental cancer model can be translated to individuals with cancer. Clin Cancer Res; 19(2); 320-6. Ó2012 AACR.

Preventing tumor escape by targeting a post-proteasomal trimming independent epitope

“…We targeted two different epitopes of SV40 large T (T-Ag) in tumors whose growth depended on T-Ag ( Anders and Blankenstein, 2013 ). The H2-K b –presented peptide IV (pIV) is dominant, with ∼11% of the CD8 + T cells in T-Ag immunized wild-type mice being pIV specific, demonstrating that the epitope is efficiently processed and presented under vaccine conditions ( Mylin et al, 2000 ).…”

IGF1R- and ROR1-Specific CAR T Cells as a Potential Therapy for High Risk Sarcomas

“…First, they directly and specifically kill IGF1R + cancer cells even at a low level of surface expression as CD8 + CTLs are capable of responding to a single antigen molecule [ 48 ]. Second, they produce TNF-α and IFN-γ cytokines, which subsequently mediate bystander elimination of stromal cells and vasculature within the tumor microenvironment [ 49 ]. Third, they persist for months and years, and proliferate in vivo as it has been shown in recent clinical trials with CD19 CARs containing 4-1BB or CD28 signaling domains [ 1 , 3 – 5 ].…”

Efficacy of CAR T-cell Therapy in Large Tumors Relies upon Stromal Targeting by IFNγ

“…Another reason for therapy failure might have been the tumor burden; perhaps, z-CAR-Ts would have been more effective against smaller tumors (27). Both antigen-dependent and -independent mechanisms can contribute to stroma destruction as a requirement for cancer eradication (28). Previous studies of TCR-mediated ATT consistently reported that tumor stroma targeting was critical to prevent tumor recurrence and that T-cell-produced IFNg needed to act on the tumor stroma (8,11).…”