ASCO 2016 Update: Beyond Checkpoint Blockade: Novel Immunotherapy Strategies for Solid Cancers

While many trials have explored checkpoint immunotherapy in combination with already-existing treatments such as chemotherapy, radiation, and other checkpoint inhibitors, the results of other, more novel approaches—which could very well foreshadow the future of immunotherapy—have also been revealed here at ASCO16.

The first trial, presented by Aung Naing, MD, and conducted with Nizar Tannir, MD, both of the MD Anderson Cancer Center, treated patients with an anti-inflammatory cytokine, IL-10, that was modified to stay active in the body longer. Despite IL-10’s anti-inflammatory properties, it also promotes proliferation of cytotoxic CD8+ T cells with potential anti-tumor activity. Patients who received IL-10 in combination with the anti-PD-1 antibody pembrolizumab appeared to respond promisingly. In kidney cancer, 50% of patients responded while the other 50% had their disease stabilize. In lung cancer, 40% of patients responded while another 40% experienced disease stabilization. Importantly, this means that none of the patients with kidney cancer or lung cancer saw their disease progress. In melanoma, 33% of patients responded, and another 33% saw their diseases stabilize. In patients from all three of these cancer types, effective treatment outcomes also coincided with increased CD8+ T cell activation.

Another trial explored the use of a bi-specific antibody, IMCgp100, which links the T cell receptor to a surface molecule on melanoma cells, making it easier for T cells to destroy them. This strategy, as explained by Mark R. Middleton, MD of the University of Oxford, induced T cell infiltration into tumors and produced durable responses in both uveal and cutaneous melanoma, and also appeared safe.

A third treatment approach, this one in hard-to-treat pancreatic cancer and presented by Nathan Bahary, MD, PhD, of the University of Pennsylvania Medical Center, targeted the activity of the immunosuppressive IDO pathway via the small molecule Indoximod in combination with chemotherapy. This approach led to a 45% RR in patients—nearly double the 23% RR achieved with chemotherapy alon—and produced two complete responses. The delayed response times suggest that they were due to immune-mediated mechanisms.

Another trial presented by Shailender Bhatia, MD, of the Seattle Cancer Care Alliance, revealed the effectiveness of G100, a molecule that activates the TLR4 pathway, which can convert “cold” non-responsive tumors into “hot” responsive tumors through the activation of anti-tumor T cells and natural killer cells, conversion of macrophages into an anti-tumor state, and the maturation of dendritic cells. TLR4 activation also promotes infiltration of immune cells into the tumor. Half the patients with the rare skin cancer Merkel cell carcinoma responded to the treatment, and four of the patients have remained relapse-free for between 13 and 27.5 months.

Finally, two other immunotherapy strategies to treat advanced solid tumors were presented by Henry Koon, MD, of the University Hospitals Case Medical Center, and Branimir I. Sikic, MD, of Stanford Medicine. The first approach—tested in a trial conducted by Jedd Wolchok, MD, PhD, of Memorial Sloan Kettering Cancer Center and an associate director of CRI’s Scientific Advisory Council and director of the CVC Trials Network—used TRX518, an anti-GITR antibody, to treat patients. Signaling through GITR can limit suppression by pro-tumor regulatory T cells and promote proliferation and activation of beneficial CD4+ and CD8+ T cells. In this phase 1 trial, four patients achieve disease control. Further analysis of this treatment’s effectiveness remains ongoing. The second trial, also a phase I, targeted the CD47 receptor that is expressed by cancer cells and helps prevent immune-mediated tumor cell destruction. At this early stage, the treatment has been well tolerated, but further dosing and efficacy studies are still being conducted.