This is the third and final blog in a mini-series of key highlights from the Third CRI-CIMT-EATI-AACR (CICON17) International Cancer Immunotherapy Conference: Translating Science into Survival (September 6-9, 2017 in Mainz/Frankfurt, Germany), prepared by our consultant Julia Holland.
Day 3: Combination Therapies, Checkpoint Inhibition and Resistance, Immunomodulators and Microbiota
The underlying molecular mechanisms for several potential combination treatment approaches were discussed throughout the first session. Ira Mellman (Genentech, San Francisco, CA, United States) opened the session by describing a new mechanism of T cell inactivation through PD-L1. After activation through PD-L1 it was found that PD-1 initiates the recruitment of the phosphatase Shp2, which in turn dephosphorylates CD28. Mellman’s results revealed that PD-1 suppresses T cell function primarily by inactivating CD28 signaling rather than through TCR signaling. This suggests, that costimulatory pathways play key roles in regulating effector T cell function and responses to anti-PD-L1/PD-1 therapy.
Mellman also described the synergistic effects of combining small molecule inhibition of MEK (e.g. cobimetinib) together with anti-PD-L1 immunotherapy. MEK inhibition reverses KRas induced suppression of MHC1 gene expression and thus increases MHC1 presentation on tumor cells. This abundance of MHCI molecules is believed to slow down T cell death by allowing chronic antigen stimulation. When combined with anti-PD-L1, the anti-tumor response is strengthened remarkably. This is currently under clinical investigation in sarcomas and colorectal cancer.
Another potential combination therapy strategy proposed by Mellman is of HPK1 and anti-PD-L1. HPK1 is a large scaffolding protein involved in multiple protein-protein interactions with its discrete mechanism and function remaining uncertain. The protein has a possible association with the MAPK pathway and mediates suppressive PGE2 receptor signaling. HPK1 might be included in the regulation of NFkB signaling in T cells and DCs or involved in the regulation of the JNK pathway. Knocking out HPK1 leads to enhanced TCR signaling by increased phosphorylation of pERK and pPLCỿ. Hence, targeting HPK1 in combination with anti-PD-L1 therapy drastically increased anti-tumor responses in several mice tumor models.
A similar type of synergy was shown for a TGF-beta antagonist combined with anti-PD-L1. Combination therapy led to increased expression of T cell effector genes and decreased expression of TGF-beta inducible Cancer-Associated Fibroblasts (CAF) genes. A high expression of CAF genes was identified for the stromal signature in bladder cancer associated with a reduced overall survival.
Sjoerd H. van der Burg (Leiden University Medical Center, Netherlands) showed recent results of the CervISA trial in which a carboplatin-paclitaxel chemotherapy regimen was used in combination with a HPV16 therapeutic peptide vaccination. It was previously reported that in HPV16-induced cancers the vast majority of tumor infiltrating cells found in mice and patients were of myeloid origin. The chemotherapy as standard of care was used to predominantly normalize the CD14+ myeloid cell count to a normal low level similar to that of a healthy person in order to administer the anti-cancer immunotherapy vaccination. Depletion of circulating myeloid cells restored the antigen specific immunity in patients and timed vaccination during chemotherapy allowed the induction of strong and sustained T cell responses. The biological and clinical responses observed in the trial are encouraging and will be made publically available soon.
Overcoming Checkpoint Immunotherapy Resistance
Sergio Quezada (University College London Cancer Institute, UK), discussed data showing that anti-CTLA-4 checkpoint immunotherapy has been shown to selectively deplete TRegs in humans. Polymorphisms in the Fc-receptor (FcR) of patients might have a huge impact on the response to anti-CTLA-4 immunotherapy. FcRs, expressed on the surface of various immune cells, tend to recognize and bind to the Fc-region of antibodies. Binding of the FcR stimulates a desired immune response. Increasing the affinity to human FcRs resulted in higher anti-tumor activity of anti-CTLA-4 monoclonal antibodies. In human cancers, CTLA-4 is preferentially expressed on tumor infiltrating TRegs, validating its relevance as a target for TReg depletion. Quezada postulated that the presence of FcR polymorphism and high mutational burden correlates with increased responses to anti-CTLA-4. His group tested systemic TReg depletion with anti-CD25, but treatment alone was not sufficient to drive anti-tumor immunity against established tumors. However, when an Fc-engineered-CD25 (mIgG2) targeting antibody was combined with an anti-PD-1 or anti-PD-L1 checkpoint inhibitor, they were able to deplete tumor infiltrating TRegs and successfully reject several established tumors in mice.
The blog mini-series can unfortunately cover only few of the exciting topics discussed during the CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference. It has been a great opportunity to learn about the latest developments and meet such dedicated researchers. It is impossible not to stay positive and excited about cancer immunotherapy.