Patient-Specific Targeting of the T-Cell Receptor Variable Region as a Therapeutic Strategy in Clonal T-Cell Diseases.

PURPOSE: Targeted therapeutics are a goal of medicine. Methods for targeting T-cell lymphoma lack specificity for the malignant cell, leading to elimination of healthy cells. The T-cell receptor (TCR) is designed for antigen recognition. T-cell malignancies expand from a single clone that expresses one of 48 TCR variable beta (Vß) genes, providing a distinct therapeutic target. We hypothesized that a mAb that is exclusive to a specific Vß would eliminate the malignant clone while having minimal effects on healthy T cells. EXPERIMENTAL DESIGN: We identified a patient with large granular T-cell leukemia and sequenced his circulating T-cell population, 95% of which expressed Vß13.3. We developed a panel of anti-Vß13.3 antibodies to test for binding and elimination of the malignant T-cell clone. RESULTS: Therapeutic antibody candidates bound the malignant clone with high affinity. Antibodies killed engineered cell lines expressing the patient TCR Vß13.3 by antibody-dependent cellular cytotoxicity and TCR-mediated activation-induced cell death, and exhibited specific killing of patient malignant T cells in combination with exogenous natural killer cells. EL4 cells expressing the patient's TCR Vß13.3 were also killed by antibody administration in an in vivo murine model. CONCLUSIONS: This approach serves as an outline for development of therapeutics that can treat clonal T-cell-based malignancies and potentially other T-cell-mediated diseases. See related commentary by Varma and Diefenbach, p. 4024.

A precision therapy against cancers driven by KIT/PDGFRA mutations.

Targeting oncogenic kinase drivers with small-molecule inhibitors can have marked therapeutic benefit, especially when administered to an appropriate genomically defined patient population. Cancer genomics and mechanistic studies have revealed that heterogeneous mutations within a single kinase can result in various mechanisms of kinase activation. Therapeutic benefit to patients can best be optimized through an in-depth understanding of the disease-driving mutations combined with the ability to match these insights to tailored highly selective drugs. This rationale is presented for BLU-285, a clinical stage inhibitor of oncogenic KIT and PDGFRA alterations, including activation loop mutants that are ineffectively treated by current therapies. BLU-285, designed to preferentially interact with the active conformation of KIT and PDGFRA, potently inhibits activation loop mutants KIT D816V and PDGFRA D842V with subnanomolar potency and also inhibits other well-characterized disease-driving KIT mutants both in vitro and in vivo in preclinical models. Early clinical evaluation of BLU-285 in a phase 1 study has demonstrated marked activity in patients with diseases associated with KIT (aggressive systemic mastocytosis and gastrointestinal stromal tumor) and PDGFRA (gastrointestinal stromal tumor) activation loop mutations.