No 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)

Natural killer (NK) cells are potent immune effector cells that can respond to infection and cancer, as well as allowing maternal adaptation to pregnancy. In response to malignant transformation or pathogenic invasion, NK cells can secrete cytokine and may be directly cytolytic, as well as exerting effects indirectly through other cells of the immune system. To recognize and respond to inflamed or infected tissues, NK cells express a variety of activating and inhibitory receptors including NKG2D, Ly49 or KIR, CD94-NKG2 heterodimers and natural cytotoxicity receptors, as well as co-stimulatory receptors. These receptors recognize cellular stress ligands as well as major histocompatibility complex class I and related molecules, which can lead to NK cell responses. Importantly, NK cells must remain tolerant of healthy tissue, and some of these receptors can also prevent activation of NK cells. In this review, we describe the expression of prominent NK cell receptors, as well as expression of their ligands and their role in immune responses. In addition, we describe the main signaling pathways used by NK cell receptors. Although we now appreciate that NK cell biology is more complicated than first thought, there are still facets of their biology that remain unclear. These will be highlighted and discussed in this review.

Background The genetic engineering of T cells through the introduction of a chimeric antigen receptor (CAR) allows for generation of tumor targeted T cells. Once expressed by T cells, CARs combine antigen-specificity with T cell activation in a single fusion molecule. Most CARs are comprised of an antigen binding domain, an extracellular spacer/hinge region, a trans-membrane domain, and an intracellular signaling domain resulting in T cell activation following antigen binding. Methods The authors performed a search of the literature regarding tumor immunotherapy using CAR modified T cells to provide a concise review of this topic. Results This review will focus on the elements of CAR design required for successful application of this technology in cancer immunotherapy. Most notably, proper target antigen selection, co-stimulatory signaling, and the ability of CAR modified T cells to traffic, persist, and retained function following adoptive transfer are required for optimal tumor eradication. Furthermore, recent clinical trials have demonstrated tumor burden and chemotherapy conditioning prior to adoptive transfer as critically important for this therapy. Future research into counteracting the suppressive tumor microenvironment and the ability to activate an endogenous anti-tumor response by CAR modified T cells may enhance the therapeutic potential of this treatment. Conclusion In conclusion CAR modified T cell therapy is a highly promising treatment for cancer having already demonstrated both promising pre-clinical and clinical results. However, further modification and additional clinical trials will need to be conducted to ultimately optimize the anti-tumor efficacy of this approach.

Adoptive cell therapy with genetically modified T cells expressing a chimeric antigen receptor (CAR) is a promising therapy for patients with B-cell acute lymphoblastic leukemia. However, CAR-modified T cells (CAR T cells) have mostly failed in patients with solid tumors or low-grade B-cell malignancies including chronic lymphocytic leukemia with bulky lymph node involvement. Herein, we enhance the antitumor efficacy of CAR T cells through the constitutive expression of CD40 ligand (CD40L, CD154). T cells genetically modified to constitutively express CD40L (CD40L-modified T cells) demonstrated increased proliferation and secretion of proinflammatory TH1 cytokines. Further, CD40L-modified T cells augmented the immunogenicity of CD40(+) tumor cells by the upregulated surface expression of costimulatory molecules (CD80 and CD86), adhesion molecules (CD54, CD58, and CD70), human leukocyte antigen (HLA) molecules (Class I and HLA-DR), and the Fas-death receptor (CD95). Additionally, CD40L-modified T cells induced maturation and secretion of the proinflammatory cytokine interleukin-12 by monocyte-derived dendritic cells. Finally, tumor-targeted CD19-specific CAR/CD40L T cells exhibited increased cytotoxicity against CD40(+) tumors and extended the survival of tumor-bearing mice in a xenotransplant model of CD19(+) systemic lymphoma. This preclinical data supports the clinical application of CAR T cells additionally modified to constitutively express CD40L with anticipated enhanced antitumor efficacy.