The New Era of Cancer Immunotherapy

Manipulating T-Cell Activity to Overcome Malignancy

Danny N. Khalil*,†; Sadna Budhu*; Billel Gasmi*; Roberta Zappasodi*; Daniel Hirschhorn-Cymerman*; Tamar Plitt*; Olivier De Henau*,‡; Dmitriy Zamarin*,†,§; Rikke B. Holmgaard*; Judith T. Murphy*; Jedd D. Wolchok*,†,§; Taha Merghoub*,†,1    * Ludwig Collaborative and Swim Across America Laboratory, Memorial Sloan Kettering Cancer Center, New York, USA
† Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, USA
‡ Department of Medical Oncology, Jules Bordet Institute, Universite Libre De Bruxelles, Brussels, Belgium
§ Weill Cornell Medical College, New York, USA
1 Corresponding author: email address: Merghout@mskcc.org

1 Introduction

Despite much recent attention to the field of cancer immunotherapy (Couzin-Frankel, 2013), the idea of recruiting the immune system against cancer predates our knowledge of the genetic basis of cancer and even modern genetics. The reason for the relative lack of attention to the field is debatable, but likely is in part due to important developments in other modes of cancer therapy such as surgery, radiation, cytotoxic chemotherapy, and most recently targeted therapy. While there are indications that ancient civilizations intentionally transferred microbes into tumors to control their growth, thereby unknowingly harnessing the immune system, modern cancer immunotherapy can be traced back to Dr. William Coley, a surgeon working in New York City who began treating cancer patients by injecting live Streptococcus pyogenes intratumorally after learning of a patient with prolonged remission of recurrent sarcoma after severe erysipelas (Coley, 1991).

In the century since the work of Coley, research in the field of cancer immunotherapy has continued mostly outside the spotlight of mainstream cancer research. While the first data from a phase III clinical trial demonstrating improved overall survival among patients with advanced cancer attributable to immunotherapy would not come until 2010 (Hodi et al., 2010), there were several instructive successes in the interim that have impacted standard of care. Cytokine therapy has been the most important such therapy for systemic disease. Interleukin-2 treatment has resulted in durable responses for patients with metastatic renal cell carcinoma and melanoma (Rosenberg, 2014; Rosenberg et al., 1994). Interferon-α has been developed for the treatment of melanoma, renal cell carcinoma, AIDS-related Kaposi sarcoma, follicular lymphoma, and hairy cell leukemia (Gajewski & Corrales, 2015; Jonasch & Haluska, 2001). The knowledge gained from the experience with these agents has been invaluable, and their role in controlling cancer remains an area of active research. They have demonstrated the extreme manifestations of attempting to engage the immune system in treating cancer, as patients have developed both severe toxicity as well as deep, durable disease control. In many ways, it was these results that motivated the strong interest in engaging the immune system with greater specificity. This resulted in a concerted effort to develop therapeutic cancer vaccines that dominated the field for more than a decade. The fact that this has yet to result in the approval of vaccination for the treatment of human cancer is instructive in itself, and while this remains an exciting field of translational cancer research, it suggests that educating the immune system to recognize disease-specific antigens, a highly effective method in preventing infectious disease, may not address the crucial barriers preventing a healthy immune system from eradicating tumors.

Although cancer immunotherapy has largely focused on the systemic control of cancer, it is important to recognize its historic contribution in the treatment of localized disease. Topical imiquimod, a TLR7 agonist, is indicated for the treatment of superficial basal cell carcinoma (Beutner et al., 1999); and the tuberculosis vaccine Bacillus Calmette-Guérin is used intravesically in the treatment of nonmuscle-invasive bladder cancer (Brandau & Suttmann, 2007).

Other standard treatments for cancer that are not always categorized as “immunotherapy” also rely, to a greater or lesser extent, on the immune system. The graft-versus-leukemia effect of allogeneic bone-marrow transplant is well known (Horowitz et al., 1990). Antigen presentation by dendritic cells (DCs) seems to be necessary for the potentially curative effect of extracorporeal photopheresis in cutaneous T-cell lymphoma (Edelson, 1999). The efficacy of antitumor monoclonal antibodies (mAbs) such as rituximab, trastuzumab) partially depends on immune-mediated destruction of targeted malignant cells even when the target is a growth factor receptor (Horlock et al., 2009; Tokuyama et al., 2008). Similarly, small molecules, including those developed to block cancer-cell signaling pathways (e.g., vemurafenib), also have profound effects on the antitumor immune response (Su et al., 2012). Along these lines, it is important to recognize that the immunologic impact of surgery, radiation therapy, and cytotoxic chemotherapy is also significant in some cases (Apetoh et al., 2007; Vittimberga, Foley, Meyers, & Callery, 1998).

The clinical success of immune checkpoint blockade and genetically engineered T cells has drawn tremendous interest. This has served not only to accelerate studies of how these tools can be implemented and improved, but it has also opened the door to investigation of new classes of immunotherapies, many of which are already in active clinical development. In this piece we provide an overview of the current state of therapeutic immune modulation in cancer, highlighting areas that we feel hold particular promise. We lay out the role of mAbs in blocking immune checkpoints and activating costimulatory molecules. This is followed by a description of adoptive T-cell therapy. We then describe a set of small-molecule inhibitors that are potentially potent immunomodulators. Finally, we review the place of radiotherapy and oncolytic virus therapy in mediating anticancer immune activity.

2 Modulation of T-Cell Activity with mAbs

After decades of research on educating the immune system to recognize specific antigens associated with cancers, primarily in the form of therapeutic anticancer vaccines, a very different approach in which inhibitory or activating immune cell receptors are targeted has recently gained interest (Fig. 1). This method uses mAbs to block inhibitory receptors or to activate stimulatory receptors on T cells and other immune cells (Table 1). This approach has proved sufficient to mediate robust antitumor activity in the absence of an agent to direct the immune response to specific antigens.