Immunotherapy and Novel Combinations in Oncology: Current Landscape, Challenges, and Opportunities

Cancer treatments have been transformed with recent advances in cancer immunotherapy.1 As monotherapies, these agents have demonstrated clinical activity across many tumor types. Further advances in the effectiveness of cancer immunotherapies will require targeting antitumor immune response at multiple levels, which may be accomplished through combination approaches. This review discusses the current landscape of cancer immunotherapy, combinations in clinical development, strategies for dose selection and trial design, and clinical pharmacology and regulatory considerations. Cancer kills over 8 million people worldwide every year and the number of diagnosed cases is expected to almost double in the next two decades.2 Surgery, radiation, chemotherapy, and targeted agents are commonly used to treat these patients, but many patients either relapse or are refractory to treatment. In addition, patients and physicians must manage a variety of side effects that have a significant impact on patients’ quality of life, which limits the use of these agents. It is well established that cancer cells can be recognized by the immune system, and it is hypothesized that the defeat of the immune surveillance system underlies the development of malignancies and the lack or loss of response to treatment.3, 4 Under normal circumstances, a functioning immune surveillance system will recognize and eliminate transformed cells. Ironically, this Darwinian process ultimately results in the selection of tumor cells resistant to processing by the immune system through loss of antigenicity, defects in antigen presentation, and decreased immunogenicity (e.g., through upregulation of PD1, a negative regulator of the immune system).5 Immune escape is also accomplished by the alteration of the tumor microenvironment,5 whereby tumor cells recruit immune-suppressive cells to promote conditions for their survival. Immuno-oncology approaches attempt to restore the immune surveillance system and activate the patient's immune system to fight their cancer. These approaches have garnered significant attention and are projected to be the new standard of care for diverse tumor types. Indeed, the clinical data of recent regulatory approvals of immunotherapy treatments including blinatumomab (BLINCYTO), ipilimumab (Yervoy), nivolumab (Opdivo), and pembrolizumab (Keytruda) across multiple cancer types demonstrate the clinical feasibility of this approach. The promise of immunotherapy to treat cancer was first realized over 100 years ago (Figure 1). In 1890, Emil von Behring and Erich Wernicke found that animals infected with diphtheria could be cured by injection of sera produced by animals immunized with an attenuated form of diphtheria, and this treatment was successfully used to treat a child with diphtheria in 1891.6 This introduced the use of serum as therapy and for the first time showed that immunity could be transferred, thereby demonstrating the clinical utility of passive immunity. The first application of immunotherapy in oncology also occurred in 1891, when William B. Coley (known as the father of immunotherapy) injected bacteria into a patient with cancer as a means of stimulating the immune system to shrink the patient's tumor, a strategy that was successful.7 Since then, significant progress has been made in the understanding and application of immunotherapy as monotherapy for cancer treatment. These agents can be classified as either active therapies that induce an immune response in otherwise nonresponsive patients or passive therapies that stimulate a patient's intrinsic immune response8 (Table 1). Active therapies include cytokines, immunomodulatory monoclonal antibodies (mAbs), and cancer vaccines, and passive therapies include BiTE antibody constructs, bispecific and multispecific antibodies, oncolytic viruses, cell-based therapies, and tumor-targeting mAbs. The checkpoint inhibitors (e.g., PD-1, PD-L1, CTLA-4, and LAG-3) are immunomodulatory mAbs that address immune escape by tumor cells that leverage normal immune-suppressive mechanisms to prevent autoimmunity and tissue damage in response to acute infection in otherwise healthy individuals, but promote tumor progression in cancer patients.9 BiTE antibody constructs have dual specificity for T cells and cancer cells and bind to an invariant component of a T-cell receptor and a specific surface antigen on a cancer cell (e.g., CD19), forcing them into proximity.10 Because they do not require a T-cell clone with a specific T-cell receptor or an MHC class I or peptide antigen for T-cell recognition, BiTE antibody constructs can overcome immune escape. Oncolytic viruses selectively kill cancer cells and stimulate the immune system (e.g., Imlygic), while dendritic cell vaccines (e.g., sipuleucel-T) involve the extraction of dendritic cells from the patient, exposure of those cells to cancer cells or antigens, and reintroduction of these now active immune cells to the patient (alternative approaches to vaccination against cancer are also under investigation).11 Adoptive T-cell therapies including CAR-T cell approaches depend on the genetic alteration of T cells to express particular antigen receptors on their surface that can recognize and kill cancer cells.12 The therapeutic use of neoantigens to stimulate T-cell responses in cancer patients also have potential, with data from mouse models showing that vaccination with neoantigens can be effective.13 Immune system modulation by antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity mechanisms has also been successfully achieved with agents targeting CD20, CD52, SLAMF7, and CD38 showing clinical efficacy. More than 15 cancer immunotherapies were approved for use as monotherapies in various solid and liquid tumor indications and three combination immunotherapies were approved as of 2015 (Table 2; refer to the United States product inserts [USPIs] for specific approved indications). Currently, the majority of approved cancer immunotherapies and those in development are biologics or cell-based therapies, as these are ideal modalities to target protein–protein interactions and signaling is a significant for the development of to their to the activity of (e.g., which are not by a multiple mechanisms of and modalities of targeted agents and and various tumor types are immunotherapies that involve various of the may the to prevent immune escape by targeting multiple mechanisms by which tumor cells by the immune system, with effects that may in patient (Figure immunotherapy combinations involve multiple immunotherapies or cancer therapies as chemotherapy, radiation, and targeted therapies (Table The and approvals of and for the treatment of cancer in and nivolumab and ipilimumab for the treatment of in 2015 the for combination The combination of and in a of in the The combination of nivolumab and ipilimumab was also than the agents. As monotherapies, these agents a in standard of in these agents were with an of for the combination of nivolumab and with and for ipilimumab and nivolumab this at the of which is not an for immunotherapy combination the for the in the of this was a for the combination of nivolumab and are checkpoint inhibitors targeting negative of the immune system, they on regulatory in the system, while and in the tumor The mechanisms of to and inhibitors may be by combination therapy (e.g., the the upregulation that may to These mechanisms are not well and combination therapy not mechanisms of that to be with agents with mechanisms of many of the current combination are of the nivolumab and ipilimumab combination into combinations of checkpoint inhibitors with vaccines, cytokines, and targeted agents are also (Table therapies may the for cancer patients, and it is expected that therapies will the standard of care for cancer but the of combinations is a approved by the for the treatment of including 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