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Immuno-oncology: The importance of combination therapies
September 2013
by Helen Sabzevari, EMD Serono  |  Email the author

For scientists and clinicians alike, the appeal of immuno-oncology is the possibility of eliciting an immune response to destroy primary and metastatic tumors, inducing tumor-specific immunological memory, resulting in the immune system's ability to "remember" tumor cells and enabling long-lasting regression and potential prevention of relapse in patients without additional treatment. Further, it also holds the ability to harness the body's own immune system to treat the disease, which could minimize toxicity and increase tolerability—an advantage that allows multiple cancer targets to be attacked simultaneously, increasing the chances of therapeutic success. Given this, immuno-oncology may turn out to be the most promising therapeutic strategy in the fight against cancer.  
Scientific evidence strongly supports the hypothesis that the innate and adaptive immune systems recognize and eliminate precancerous lesions in a process known as immunosurveillance. This natural immune response relies on the recognition of specific tumor antigens, such as viral proteins present in tumors, mutated proteins in the form of oncogenes as well as non-mutated, but highly expressed "self" proteins found on the surface of cancer cells. As tumors progress toward greater genetic instability, however, through natural selection they evolve an impressive armamentarium of immunosuppressive mechanisms (e.g., loss of tumor antigen) that allow the tumor to escape immune detection and progress unimpeded toward malignancy.  
Significant scientific and technological advancements that have been made to understand these mechanisms have recently culminated in the regulatory approval of two cancer immunotherapies: a therapeutic cancer vaccine, sipuleucel-T, for hormone-refractory prostate cancer, and a T-cell potentiating monoclonal antibody, anti-CTLA-4 (ipilimumab), for melanoma. With these historic milestones and the recent publication of very promising treatment strategies for malignant melanoma, immuno-oncology is now gaining wide acceptance as a promising therapeutic strategy due to its unique potential to generate durable clinical responses in patients. Additionally, there has been a resulting proliferation of cancer immunotherapies in the clinical pipeline.
A new treatment paradigm
Standard cancer treatment regimens such as chemotherapy typically follow the same pattern: an initial clinical response and brief period of remission, followed by rapid disease progression. The reason these regimens are only marginally effective is because they fail to fully eliminate all of the cancer cells, and those that remain are rendered highly resistant to treatment.  
In contrast, immunotherapy has the potential to induce long-term clinical responses, as evidenced by the ability of effective immunotherapies to "raise the tail" of survival analysis curves. Strikingly, responses to immunotherapy are often observed months or even years after treatment has been discontinued, suggesting that antitumor immune responses evolve over time and are long-lived. Furthermore, because the immune system can eliminate tumor cells in a highly selective manner, immunotherapies are expected to offer improved safety and tolerability in comparison to direct cytotoxic therapies that not only eliminate tumor cells, but also cause significant collateral damage to normal tissues.
Identifying effective combination therapy regimens that are capable of breaking tumor immune tolerance may maximize the therapeutic benefit of cancer immunotherapies. For example, this may involve combining agents that actively stimulate antitumor immunity such as cancer vaccines with agents that inhibit the various mechanisms of tumor immune suppression, such as checkpoint inhibitors and/or agents that target cancer stem cells with the goal of achieving cures.  
Immunotherapies that target various aspects of cancer immunology not only have a strong potential for immunotherapy-specific combination therapies, but they are also attractive combination partners for existing standard-of-care treatment options, including chemotherapy and radiation. Until recently, many of these therapies were considered incompatible with immunotherapy because these treatments can potentially cause systemic immune suppression. It is now clear, however, that many standard-of-care therapies have positive effects on the tumor's immunological environment. For example, both chemotherapy and radiation have been shown to render the tumor cells more readily recognizable by the immune system. Furthermore, certain chemotherapies and targeted therapies are known to selectively deplete specific immunosuppressive cell types (e.g., regulatory T cells, myeloid-derived suppressor cells) that reside within tumors and prevent an effective immune response. These positive immunomodulatory properties of many standard-of-care therapies may therefore open a "window of opportunity" for enhancing the efficacy of cancer immunotherapy.  
Promising therapeutic strategies  
As the scientific and clinical communities gain a deeper understanding of the molecular basis of tumor immunology, it is becoming increasingly clear that if used in various combinations or earlier in disease, current and future immunotherapies hold the potential to transform cancer treatment. There are various immunotherapeutic strategies that are actively being explored, a few of which are described below.  
1. Tumor immune tolerance
Fundamental to the function of the immune system is its ability to discriminate "self" from "non-self." In a process known as self-tolerance, normal cells that make up the body's tissues and organs are recognized as self and therefore ignored by the immune system, whereas foreign organisms, such as bacteria or viruses, are recognized as non-self, attacked and removed from the body. By default, cancer cells are viewed as self because they arise from normal tissues.
However, as described above, cancer cells can also produce abnormal or mutant versions of proteins that elicit an immune response through immunosurveillance.   Among the immune cells capable of mounting such an attack, the cytotoxic CD8+ T cells (killer T cells) are most effective. Therefore, to avoid immune elimination, tumors evolve a network of immunosuppressive mechanisms that are directed against killer T cells, thus generating a state of tumor-immune tolerance that allows them to grow and metastasize unimpeded. These mechanisms of immunosuppression that inhibit the function of T cells do not work in isolation, but rather they are tightly intertwined. Consequently, therapies targeting these pathways lend themselves to combination therapy. As a strategy for immunotherapy, blocking the mechanisms of tumor immune tolerance may reinvigorate the natural antitumor immune response and/or enhance the efficacy of other immunotherapies, such as cancer vaccines, when used in combination.  
2. Cancer vaccines
Similar to vaccines that are directed against infectious micro-organisms, therapeutic cancer vaccines seek to stimulate a specific immune response against the tumor and generate immunological memory to achieve long-term protective effects. Development of cancer vaccines involves the identification of those tumor antigens that are capable of generating robust antitumor immune responses and formulating these antigens into a final therapeutic product that displays optimally enhanced immunostimulatory properties.  
3. Cancer stem cells
Cancer stem cells represent a rare population of tumor cells required for perpetuating tumor growth. Additionally, cancer stem cells can migrate from the primary tumor, enter into the blood stream and travel to distant anatomic sites, resulting in the formation of metastases. Due to their limited cell cycling and multiple detoxifying mechanisms, cancer stem cells are resistant to standard chemotherapies and small-molecule drugs. They also hide in protective niches and upregulate the expression of important surface molecules that allow them to evade immune surveillance. As a result, cancer stem cells have been implicated as the main cause of disease recurrence. Therapies that eliminate cancer stem cells are thus expected to translate into a realistic potential for achieving long-term cures.  
The recent clinical success of two very distinct cancer immunotherapies has renewed interest in a field that holds great promise for transforming the treatment landscape by harnessing the patient's own immune system to fight cancer. There are various immunotherapeutic strategies being developed to elicit an antitumor immune response, such as cancer vaccines and monoclonal antibodies. These immunotherapies may be most effective when used in combination with other immunotherapies and/or established therapies. Combining therapies that target multiple aspects of the disease process may be the key to clinical success.  
Dr. Helen Sabzevari is senior vice president of immuno-oncology and global research and early development at EMD Serono. Her operational responsibility includes discovery, translational research and early development in the field of cancer vaccines and cancer immunotherapy. Sabzevari received her Ph.D. in cellular and molecular immunology and completed her post-doctoral work at the Department of Immunology at The Scripps Research Institute.



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