Immuno-oncology promises to destroy both primary and metastatic tumors using an immune-based response. Even more exciting is the possibility of building tumor-specific immunological memory, which means that the body will actually build immunity toward future tumor cells, thus resulting in a lasting remission. By using the body’s own immune systems, oncologists can avoid much of the toxicity involved with traditional oncological treatments and increase treatment tolerability. Thus, multiple cancer targets can be attacked at once to produce greater therapeutic results.
The use of immuno-oncological techniques represents a new approach to cancer treatment altogether. Standard regimens, including chemotherapy and radiotherapy, follow a similar pattern that involves an initial clinical response followed by brief remission and then rapid progression of the disease. This cycle suggest that these regimens are only marginally effective, which is likely due to the inability of traditional approaches to eliminate all cancer cells. Thus, the cells that remain become resistant to the treatment modality employed.
The Potential of Immuno-Oncology in Combination Therapies
In contrast to traditional treatment methods, immuno-oncology usually results in a long-term clinical response. This fact is demonstrated by the “raise the tail” effect that certain immunotherapies have on the survival analysis curve. The responses elicited by immunotherapy tend to be observed for months, if not years, after doctors cease administering the treatment. Antitumor responses created by immuno-oncology are thus long-lived and may even evolve over time to maintain their effectiveness.
For this reason, immunotherapies have emerged as strong candidates for combination therapies. In fact, many biopharmaceutical firms are testing their immuno-oncology products with other immunotherapies and existing standards of care. Not long ago, treatments like chemotherapy and radiotherapy were thought to be incompatible with immunotherapies because of the potential for systemic immune suppression. However, research has shown that a number of standard therapies actually have positive effects on the body’s ability to fight off tumors.
Both chemotherapy and radiation can make tumor cells more easily recognizable by the immune system and trigger an immune attack. A handful of chemotherapies can selectively destroy specific types of immunosuppressive cells, such as myeloid-derived suppressor cells and regulatory T cells. These cells live within tumors and prevent an effective response from the immune system. Using these treatments could enhance the effects of cancer immunotherapy.
Immuno-Oncology Used in Combination with Standard Care
In particular, the use of PD-L1 inhibitors with chemotherapy could bolster the immune response to cancer cells. Therapeutic approaches involving these two different treatments have been studied extensively using animal models, and human clinical trials will likely begin in the near future. According to preclinical studies, this experimental approach could elicit positive additive effects and generate a stronger immune response while driving up overall survival rates.
In terms of radiation, researchers have found that radiotherapy in patients with colorectal and prostate cancer can increase the survival rate of T cells and make them more effective at targeting tumor cells. Radiation may also make cancer cells release certain molecules that recruit T cells to the tumor site or cause natural killer cells to become more active. These effects could make immunotherapies that trigger similar processes have a stronger therapeutic effect.
Pairing Immuno-Oncology with Other Treatment Modalities
Researchers are also looking at the possibility of combining immunotherapies with other therapies, such as small-molecule targeted therapy. Many targeted therapies, like standard-of-care treatments, have an immunomodular effect, such as T cell proliferation and increased responsiveness to tumor antigens. Thus, they have the similar potential for additive effects.
The most promising candidates among small molecule options include BRAF and MEK inhibitors, both of which have several immunomodulatory properties that could benefit PD-L1 inhibition immunotherapies. Research has shown that BRAF inhibitors, whether used alone or with MEK inhibitors, increase tumor antigen expression in patients with metastatic melanoma. In addition, these small molecules can increase T cell infiltration and increase PD-L1 expression in the same patients.
Another potential for combination therapies involves two different forms of immuno-oncology. Both preclinical and early clinical studies suggest that two immunotherapies that trigger different pathways can be used in unison for greater effect. Two immunotherapies that inhibit nonredundant pathways can have a synergistic effect when used together. For example, PD-L1 and CTLA-4 inhibitors have been shown to have a stronger effect when used together than when used alone.
Researchers believe that this combination therapy could help remove some of the inhibition on adaptive immune responses for strong antitumor attacks. By inhibiting CTLA-4, T cells become activated and proliferate because CTLA-4, an inhibitory receptor, can no longer interact with CD86 and CD80. Then, the activated T cells enter the tumor microenvironment and trigger the release of interferon gamma, which in turn results in the upregulation of PD-L1 by tumor and immune cells. PD-L1 binds to PD-1 on T cells in an effort to stop the normal immune reaction. However, PD-L1 inhibitors prevent this action. Thus, T cells may remain activated longer and have a greater antitumor immune response.