Cellular therapy for cancer: Let there be light

Abstract

Recent articles and the reviews by Shook and Campana (1) and by Casucci et al. (2) in the latest and the current issue of Tissue Antigens, respectively, make it clear that the dawn of targeted cellular therapy is well upon us. The limited benefits and often devastating side effects of conventional chemotherapeutic agents as treatment for cancer have long encouraged the search for more targeted agents. The ‘poster child’ for such targeted agents, of course, is Gleevec (imatinib), which has had spectacular benefits in the treatment of chronic myelogenous leukemia (3). Although enormous research and investment efforts have brought forth additional targeted small molecules for other cancers, their benefits have been less dramatic, and few have been able to eradicate malignancy (4). It has long been evident that the immune system has the potential to be a vastly superior means of specifically targeting tumors compared with small molecules. Both antibodies and T-cell receptors are exquisitely specific for the target antigens, and monoclonal antibodies such as Rituximab have been a major success story in the battle to produce effective targeted therapies for cancer (5). It is now clear that it will be possible to use targeted cellular immunotherapy to produce benefits in cancer treatment that could go well beyond those that can be obtained with small molecules or even monoclonal antibodies (6, 7). Cellular immunotherapies, unlike monoclonal antibodies or targeted small molecules, have the advantage of active mobility, with the potential to seek out tumor cells by trafficking through multiple tissue planes (Table 1). On arrival at tumor sites, these cells can bring to bear on tumor cells and their supporting environment a multiplicity of cytotoxic and inhibitory effector functions that transcend the limitations of small molecules and antibodies. Moreover, immune cells are capable of in vivo expansion and long-term persistence, so that a single dose of relatively small numbers of appropriately targeted effector cells may be sufficient to control or eradicate tumor for the lifetime of the patient (1). There are already many thousands of examples of successful use of donor lymphocyte infusions (DLI) to treat relapse after stem cell transplantation, and there are also substantial cohorts of patients who have had benefits from T cells directed by their native or by artificial chimeric receptors to leukemia, lymphoma and melanoma associated antigens (8–11). Successes in other solid tumors have been more anecdotal, but are steadily increasing in number and predictability (12–14). Less well developed are therapies making use of natural killer (NK) cells, whose potency Table 1 Intrinisic differences between strategies to treat cancer by cellular immunotherapy, monoclonal antibodies and targeted small molecules