Tumor-targeted T cells modified to secrete IL-12 eradicate systemic tumors without need for prior conditioning

Abstract

Adoptive cell therapy with tumor-targeted T cells is a promising approach to cancer therapy. Enhanced clinical outcome using this approach requires conditioning regimens with total body irradiation, lymphodepleting chemotherapy, and/or additional cytokine support. However, the need for prior conditioning precludes optimal application of this approach to a significant number of cancer patients intolerant to these regimens. Herein, we present preclinical studies demonstrating that treatment with CD19-specific, chimeric antigen receptor (CAR)-modified T cells that are further modified to constitutively secrete IL-12 are able to safely eradicate established disease in the absence of prior conditioning. We demonstrate in a novel syngeneic tumor model that tumor elimination requires both CD4 ؉ and CD8 ؉ T-cell subsets, autocrine IL-12 stimulation, and subsequent IFN␥ secretion by the CAR ؉ T cells. Importantly, IL-12-secreting, tumor-targeted T cells acquire intrinsic resistance to T regulatory cell-mediated inhibition. Based on these preclinical data, we anticipate that adoptive therapy using CAR-targeted T cells modified to secrete IL-12 will obviate or reduce the need for potentially hazardous conditioning regimens to achieve optimal antitumor responses in cancer patients. (Blood. 2012;119(18): 4133-4141)

miR-155 augments CD8 + T-cell antitumor activity in lymphoreplete hosts by enhancing responsiveness to homeostatic γ c cytokines

“…These findings have parallels in CD4 + T cells, where miR-155 is essential for longterm maintenance of T reg cells in lymphoreplete, but not lymphodepleted, mice (20). Other strategies to potentiate adoptive T-cell therapy in the absence of lymphodepletion have been recently proposed, such as PD1 blockade in the presence of IL-2/anti-IL-2 antibody complexes (32) or overexpression of IL-12 in tumorreactive T cells (33). However, it is unclear whether such approaches can replace both lymphodepletion and cytokine support.…”

Improving Chimeric Antigen Receptor-Modified T Cell Function by Reversing the Immunosuppressive Tumor Microenvironment of Pancreatic Cancer

“…36 Additionally, CAR T cells themselves have been modified by the incorporation of co-stimulatory endodomains such as CD28, 4-1BB, and OX40, 37,38 though our results suggest that this is likely insufficient to provide long term in vivo benefit at the tumor site ( Figure S1). Other modifications include the transgenic expression of Th1 cytokines to promote autocrine growth 36,[39][40][41] or the incorporation of a dominant-negative TGF-b receptor, which sequesters this tumor-produced immunosuppressive cytokine. 42,43 Our approach extends upon the dominant-negative receptor concept by inverting a soluble immunosuppressive signal present in the tumor microenvironment into one that is immunostimulatory (4/7 ICR).…”

New insights into IL-12-mediated tumor suppression

“…The latter approach has been used to deliver CD8 þ T cells specific for melanoma antigens [102][103][104] or engineered to express a chimeric antigen receptor (CAR) against CD19 in B-cell lymphomas. 105 The administered IL-12 was found to activate myeloid cells by increasing the expression of Fas and cross-presentation, leading to the stimulation of tumor antigen-specific CD8 T cells and regression of established tumors 102,106 (Figure 1). More recently, the development of novel approaches that direct IL-12 activity to the tumor site focus on immunocytokines, for example, the fusion of the cytokine to an antibody that binds specifically to the tumor vasculature, 107,108 or to exposed deoxyribonucleic acid (DNA) in the necrotic core of a tumor.…”