Combination therapies on the rise: Reflections from Immunotherapy World 2017
Back in October of 2016, Christelle Johnson provided an excellent blog, The state of Combination Therapies in Immuno-Oncology. This emphasis on combination strategies continues to resonate throughout the scientific community and has been highlighted at several recent conferences. During Immunotherapy World (January 2017), it was even stated that the field would ultimately move “entirely” to combination therapies. Nonetheless, as evidenced by the sheer number of immunotherapy combination trials in process, it’s still clear that biopharma companies are still working to determine what combination of therapies will be most effective. Investigators are still pondering, “What is the optimal method to leverage the power of the immune system in the combination therapy context?”
Previously, less consideration was given to the rationale for these immuno-oncology (IO) combinations. For some cancers, certain immune modulators (anti-PDL1 or anti-PD1) have become the standard of care. Yet, as these monotherapy approaches have stalled in particular tumor types and certain patient populations, a synergistic approach to further boost the immune system is needed. Thus, companies want to improve upon their foundational drug with a successful, impactful combination. Investigators are now putting forth well-thought-out tactics looking closely at the potential drug’s mechanism of action. The following are just a few examples of combinations that are currently a part of the exponential rise in these trials and the logic behind them.
This is a rational design as chemo has several immunomodulatory effects, such as helping to reduce the number of immune suppressor cells including T regulatory cells and myeloid-derived suppressor cells (MDSCs). Also, chemo has been found to result in increased presentation of tumor antigens or neoantigens.
An example of this approach includes combining a checkpoint inhibitor (CPI) with a vascular endothelial growth factor (VEGF) inhibitor. VEGF promotes immune suppressor cells, so blocking this action may allow the cytotoxic T-cells to takeover and attack the tumor.
Another targeted therapy being exploring in combination is a MEK inhibitor, which inhibit mitogen-activated protein kinase kinase enzymes. By inhibiting this kinase in animal models, intratumor T-cells can accumulate (T-cells are activated and live longer) and this agent also results in class I MHC upregulation enabling tumor cells to be “more visible” targets.
Other examples include agonists such as an inducible T-cell co-stimulator (ICOS) agonist. This therapy delicately stimulates T effector cells in the tumor, while selectively reducing T regulatory cells.
These agents were designed to bind both the T-cells and tumor cells simultaneously. Bi-specific antibodies result in T-cell activation and proliferation to kill tumor cells. A benefit is that they work without the requirement of MHC peptide complex presentation by tumor cells.
Combination trials have also been proposed using an oncolytic virus paradigm. These genetically engineered viruses (such as herpes simplex-1) infect and replicate within tumor cells causing them to burst. They have shown strong efficacy alone, but combinations with CPIs may be shown to be even more advantageous.
This personalized approach has recently entered the clinical trial market and is being combined with immune modulators (NEO-PV-01). Powered by genomic innovations, tumor-specific mutations are identified in each patient’s specimen and used to create a vaccine from a unique neoepitope and delivered through DNA, RNA, or peptide modalities.
Does increased efficacy come at the cost of increased toxicity?
While proving to be more effective, combination trials in melanoma patients receiving Opdivo and Yervoy have also shown a significant increase in Grade 3/4 Adverse Events (AE) as compared to either agent alone. Likewise, Atezolizumab and Vemurafenib trials have also experienced an increase in AEs resulting in a high percentage of patients stopping treatment (Larkin et al. 2015 NEJM and Chapman et al. 2011 NEJM). The toxicities associated with these combinations can have debilitating effects and can include dermatitis, pneumonitis, hepatitis, ocular toxicity, colitis, neuropathy, and thyroiditis. Thus, managing the AEs and toxicities is a critical challenge in developing a combination strategy. Considerations of the proper dose and schedule selection (minimum and maximum effective dose) become more pressing. Additionally, what is the optimal treatment duration? Further, it will also be critical to understand the individual AEs contribution of each study component.
The good news is…
As witnessed during the Immunotherapy World panel discussions, pharma leaders recognize the obstacles of combination therapy and are taking these on with the appropriate mindset. They are deeply investing in translational studies, as the importance of digging into the data is ostensible. One director from a leading pharmaceutical company stated, “A trial without a translational component is a waste.” These investigators are aiming high. They want to see not just incremental progress with combinations, but “leaps and bounds” in clinical responses. As they strive for the best approach, the question remains, how can they prioritize the large variety of options for combinations? Leaders in the field point to the significance of taking a very careful, analytical look at the data coming off the clinical trials and also vigilantly interrogating the preclinical and model studies performed. These retrospective datasets can provide a “goldmine” or wealth of knowledge to frame their designs. Utilizing these large datasets will allow pharma to refine patient populations and properly inform effective combinations. Finally, these goals will require a collaborative scientific environment and working together. As stated by one investigator, “The best combination may be the worst business model.” Partnerships within biotech, pharmaceutical, and academic sectors will prove invaluable more than ever before.