Volume 3, Issue 5, Pages 431-437 (May 2003) Adoptive immunotherapy: Engineering T cell responses as biologic weapons for tumor mass destruction  William Y Ho, Joseph N Blattman, Michelle L Dossett, Cassian Yee, Philip D Greenberg  Cancer Cell  Volume 3, Issue 5, Pages 431-437 (May 2003) DOI: 10.1016/S1535-6108(03)00113-2

Figure 1 Critical checkpoints and pitfalls in adoptive T cell immunotherapy Following selection of a target antigen, T cells are stimulated in vitro, and reactive cells isolated and expanded to large numbers. After infusion into patients, the T cells must persist, retain function, and localize to tumor sites to be effective. Failure to support in vivo survival can result in apoptosis of the transferred cells, which interferes with efficacy. Normal tissues may also express the targeted antigen, and strategies to avoid injury to such tissues must be considered. Cancer Cell 2003 3, 431-437DOI: (10.1016/S1535-6108(03)00113-2)

Figure 2 Potential genetic modifications of T cells to enhance adoptive immunotherapy Specificity: T cells can acquire the desired specificity and affinity for the selected target antigen by introduction of either defined TCR chains or chimeric antigen receptors with antigen binding domains fused to intracellular signaling domains. Survival: Regulated growth/survival signals delivered following target recognition can be provided by restoring costimulatory signals via CD28 or introducing chimeric cytokine receptors that can be triggered by cytokines produced by T cell activation. Localization: For tumor eradication, T cells can be directed to tumors in tissues by expression of tissue-specific chemokine receptors such as CXCR4. Effector function: Intracellular signals such as those mediated via Cbl-b that normally inhibit T cell activation signals may be blocked to sustain effector functions, including cytokine production and cytolysis, promoting effective antitumor responses. Cancer Cell 2003 3, 431-437DOI: (10.1016/S1535-6108(03)00113-2)