Discover what a future with precision medicine looks like at Penn Medicine.

Current approaches to adoptive T cell therapy are limited by the difficulty of obtaining sufficient numbers of T cells against targeted antigens with useful in vivo characteristics. Theoretically, this limitation could be overcome by using induced pluripotent stem cells (iPSC) that could provide an unlimited source of autologous T cells. However, the therapeutic efficacy of iPSC-derived regenerated T cells remains to be demonstrated. Here we report the first successful programming of T-cell receptor (TCR) transgenic CD8+ T cells into pluripotency. As part of the work, we established a syngeneic mouse model for evaluating in vitro and in vivo antitumor reactivity of regenerated T cells from iPSC bearing a rearranged TCR of known antigen specificity. Stably TCR retained T cell-derived iPSC differentiated into CD4+CD8+ T cells that expressed CD3 and the desired TCR in vitro. Stimulation of iPSC-derived CD4+CD8+ T cells with the cognate antigen in the presence of IL-7 and IL-15 followed by expansion with IL-2, IL-7 and IL-15 generated large numbers of less-differentiated CD8+ T cells with antigen-specific potent cytokine production and cytolytic capacity. Furthermore, adoptively transferred iPSC-derived CD8+ T cells escaped immune rejection, mediated effective regression of large tumors, improved survival and established antigen-specific immunological memory. Our findings illustrate the translational potential of iPSC to provide an unlimited number of phenotypically defined, functional and expandable autologous antigen-specific T cells with the characteristics needed to enable in vivo effectiveness.

It may largely be the emotional support of marriage, rather than any economic advantages, that produces health benefits.

Stage 3 invasive breast cancer survivor Kathy tells what her cancer journey was like and what has helped her move forward.

Melanoma differentiation–associated gene 5 (MDA-5, IFIH1), a cytosolic innate pattern recognition receptor, functions as a first line of defense against viral infection by sensing double-stranded RNA. Ectopic expression of MDA-5 has been shown to induce cancer cell death, but the mechanism of action by which MDA-5 exerts these cytotoxic effects is unclear. Here, we demonstrate that ectopic expression of MDA-5 via replication-incompetent adenovirus (Ad.Mda-5) initiates multiple signaling cascades, culminating in cytotoxicity and type I IFN production in mouse and human prostate cancer cells. This intrinsic dual activity of MDA-5 required the adaptor protein IFNβ promoter stimulator 1 (IPS-1, MAVS) and could be functionally uncoupled. MDA-5 lacking N-terminal caspase recruitment domains (CARD) engaged an intracellular death program in cancer cells but was unable to efficiently stimulate the expression of IFNβ. In contrast to cancer cells susceptible to MDA-5–mediated cytotoxicity, normal cells were highly resistant and instead developed a robust type I IFN response. Strikingly, intratumoral delivery of Ad.Mda-5 led to regression of preestablished prostate cancers and development of long-lasting antitumor immune memory, which was primarily attributed to the activation of tumor-reactive cytotoxic T lymphocytes and/or natural killer cells. Using the CARD-truncated MDA-5 mutant, silencing of IPS-1, and antibody blockade of the IFNα/β receptor, we further demonstrate that type I IFN signaling was crucial for in situ MDA-5–induced protective antitumor immunity. Therefore, deliberately targeting the evolutionarily conserved MDA-5–IPS-1 antiviral pathway in tumors can provoke parallel tumoricidal and immunostimulatory effects that bridge innate and adaptive immune responses for the therapeutic treatment of cancer. Cancer Res; 76(8); 1–11. ©2016 AACR.