Can we use monoclonal antibodies to help T cells fight tumors

Current technology allows us to manufacture MAb with relative ease against a variety of cellular targets. Depending upon circumstances, MAb binding with their cognate Ag on a cell surface can block, enhance or redirect cell function. For tumor immunologists this raises interesting possibilities for meddling with, and hopefully improving upon, existing effector cell /tumor interactions to enhance tumor killing. Two papers in this issue of Cytotherapy address this topic. Immunologic checkpoint blockade is emerging as one of the more promising strategies in cancer immunotherapy. Of these approaches, MAb directed to CTLA-4 appear to be the most clinically relevant [1 /3]. Passive administration of antagonist MAb to this inhibitory molecule produced significant anti-tumor responses. Interestingly, clinical trials with CTLA-4 showed that a minority of patients had corticosteroid-responsive skin rashes, colitis and hypophysitis (so-called ‘immunologic breakthrough events’). These serve as proof of the principle that the MAb releases normally quiescent T cells from inhibition. An analogy used to describe CTLA-4 blockade is that of an automobile that has had its brakes disabled (J. Allison, personal communication). When the T-cell receptor is engaged (ignition started) and CD28 binds to B7-1 (accelerator pressed), the result is unopposed activation in the absence of CTLA-4 activity. The paper by Zhong et al. [4] serves to remind us that it may be important to try and ‘steer’ the resulting activated T cells toward an immunologic target of interest and away from selfmolecules that might result in toxicity. Zhong et al. [4] have devised a clever means of in vitro immunization by inducing differentiation of AML blasts with cytokines and allowing the resulting DC to present endogenous Ag to T cells present in the peripheral blood samples. When T cells engage the leukemic Ag-presenting DC they form an immune synapse of their T-cell receptor with MHC molecules on the DC. Ligation of B7-1 (CD80) on the DC with CD28 on the T cell follows, providing a strong co-stimulatory signal that completes T-cell activation and induces proliferation. The blockade by antiCTLA-4 prevents the normal engagement of CD80 by CTLA-4, interrupting down-regulatory signals, thereby increasing the amplitude of the final immune response. Recently, CTLA-4 has also been found expressed on CD4 , CD25 , CTLA-4 , forkhead box P3 (Fox-P3)expressing regulatory T cells (Treg). Treg are being increasingly viewed as major controllers of the immune response ‘thermostat’. While there are good reasons for the immune system to fine-tune the potentially serious tissuedamaging effects of proliferating cytotoxic T cells, such mechanisms could clearly limit the ability of autologous T cells to exert anti-tumor immunity. Blockade of CTLA4 by MAb is an attractive way to enhance anti-tumor immunity because it should effectively enhance the T-cell response by two mechanisms, promoting effector cell expansion and interfering with natural suppressors. Zhong et al. [4] found that CTLA-4 blockade produced a sevenfold increase in cytotoxic T cells capable of killing autologous AML. Their results suggest it would be worth scaling up the approach to generate autologous leukemiaspecific T cells for adoptive therapy of AML. In the second paper, Kornacker et al . [5] used bispecific MAb to improve the targeting of killer cells to the tumor. The effector cells they used (cytokine-induced killer T cells; CIK cells) are easily grown in vitro from T cells and are already being tested in clinical trials. While showing