Anti-tumor cytotoxic T lymphocytes targeting solid tumors: ready for clinical trials.

Most of the clinical data supporting the therapeutic use of adoptively transferred immune cells in solid cancers are derived from the treatment of virus-associated malignancies or melanoma (1,2). Effective immune targeting of less immunogenic solid tumors, including both carcinomas and sarcomas, has remained exceptional. While there is a general agreement that immune effector cells are ineffective at eliminating large solid tumors, immunotherapy may have a role in preventing systemic relapse after conventional treatment. Many solid tumors have striking initial responses to current multimodal therapies, but these are almost inevitably followed by systemic recurrence from residual tumor cells that have maintained the capacity to re-establish tumor growth. These micrometastatic, potentially chemoresistant and quiescent cells may provide adequate targets for anti-tumor immunotherapy. However, the key question remains of how we can induce tumor antigen-specifi c and highly avid T-cell clonotypes that can break tolerance against these cells and that functionally persist within the memory pool to ensure longlasting protection against tumor recurrence. Montagna et al. (3) have now obtained the fi rst clinical evidence that infusions of ex vivo -generated autologous anti-tumor cytotoxic T cells are safe in patients with advanced solid tumors. Their principal strategy builds on the ability of the individual patient ’ s tumor cells, together with professional antigen presentation by dendritic cells, to prime and expand tumor antigen-specifi c T cells (Figure 1). For this purpose, early passage tumor cell lines were successfully generated from all patients and used as source of tumor antigen. While this method is time-consuming and tedious and requires adequate biopsy material from every patient, it has substantial advantages over the use of more easily available synthetic peptides. First, anti-tumor cytotoxic T lymphocyte (CTL) responses against irradiated autologous tumor cells refl ect a broader repertoire of antigen specifi cities, increasing the likelihood of generating T-cell clonotypes that can recognize autologous viable tumor cells. Second, the approach is not limited to peptide presentation on individual major histocompatibility complex (MHC) molecules and thus allows inclusion of patients regardless of their HLA types. Third, irradiation of tumor cells for in vivo co-cultures may enhance their immunogenicity and thus enable presentation of tumor-associated antigens in an appropriate infl ammatory context for inducing effective T-cell responses (4). The identity of the antigens recognized by the CTL expanded with this technology could be very informative and lead to the generation of T cells that interact with relevant target antigens beyond individual patient tumors. A potential risk of this approach is the induction of autoreactive T-cell responses that cause clinical graft-versus-host disease (GvHD)-like immune reactions (3). Reassuringly, in this report none of the six patients receiving autologous CTL infusions, even at increasing doses of  1 10 9 CTL/infusion, experienced toxicities compatible with autoimmune reactions. Besides the requirement of isolating and expanding T cells that interact effectively with tumor-associated antigens, successful application of adoptive T-cell therapy relies on strategies that augment the in vivo survival and function of tumor-reactive T cells. In fact, the ability of T cells to persist in vivo has been correlated with therapeutic effi cacy in most studies (5). Following the observation that homeostatic T-cell proliferation induced by lymphopenia can elicit anti-tumor autoimmunity (6,7), pharmacologic lymphodepletion is now used widely to enhance the function of adoptively transferred T cells. In addition Cytotherapy, 2012; 14: 4–6