Gene-Product Auto-Targeting to Tumor Vessels

Project Summary Treatment options are limited and prognosis is poor for patients with recurrent or metastatic sarcoma. Both soft tissue sarcoma and osteosarcoma most frequently metastasize to the lungs and are often resistant to cytotoxic chemotherapy. Novel treatment options such as immune therapy are urgently needed for long-term control and elimination of metastatic disease. In that regard, both T cell (CAR-T and TILs) therapy and immune checkpoint blocking therapy have advanced to clinical applications in other types of tumors. In fact, wildtype IL12-armed T (CAR- or TIL) cells is more powerful in eliminating tumors than T cells alone in both preclinical tumor model or clinical trial because IL12 polarize T cells to the Th1 phenotype, boost effector T cells, downregulate angiogenesis, remodel the extracellular matrix, and alter levels of immune-suppressive cytokines. One urgent challenge for either CAR-T or wildtype IL12-armed T cell therapy is adverse effects. The CAR-T cells causes severe cytokine release syndrome (CRS) and wildtype IL12 causes liver toxicity. To safely use IL12, the key is to target the IL12 gene and its transcribed/translated gene product to the tumor. To that end, we have invented a novel tumor-targeted IL12 gene (ttIL12 or CHP-IL12) that encodes the p35 subunit and p40-VNTANST fusion subunit. This first generation of ttIL12 received US issued patent(US9657077B2). Different from wildtype IL12, ttIL12 therapy is also more effective in reducing myeloid- derived suppressor cells (MDSC) and FoxP3Tregs. High levels of MDSC and FoxP3 expression are associated with poor survival amongst sarcoma patients. To address the adverse effect of T cells, the applicant has invented the second generation of ttIL12 therapy— cell membrane anchored ttIL12 (attIL12)-T cell therapy (PCT/US2017/055645; UTSC.P1424US.P1). Arming T cells (CAR-T, autologous T, or TILs) with this attIL12 has potential to reduce the risk of CRS because this attIL12-T cells seems no longer induce CRS cytokine expression and avoids T cells stall in lungs but rather accumulates in tumors. The safety, efficacy, and the immune mechanism of this attIL12-armed T cell therapy will be investigated in this application. This application is novel and impactful because a novel and safe T cell therapy will be investigated.