Biomarker Study of PDR001 in Combination With MCS110 in Gastric Cancer

<Background>

1. Current status of treatment options in advanced gastric cancer.
2. Current status of immunotherapy development in gastric cancer

• Harnessing immune system to fight against cancer cells is one of highlighting strategy in new drug development in almost all kinds of solid tumor including gastric cancer.
• In PD L1expressing gastric cancer, the anti-PD1 antibody monotherapy (pembrolizumab) shows the antitumor efficacy. (Bang YJ et al. 2015)
• Anti-PDL1 antibody (Avelumab) used in the first-line maintenance setting or 2nd-line setting of biomarker-unselected gastric cancer also shows promising antitumor efficacy (Chung HC et al. ECCO/ESMO 2015, Oh DY et al. ASCO GI 2016)
• There are many clinical trials using immune-oncology (IO) agents are ongoing in 1st-line setting, 2nd-line setting, 3rd-line setting and refractory setting. Several strategies are being used, that is, IO monotherapy in biomarker-selected population, IO+IO combination, IO+cytotoxic chemotherapy , and IO+other targeted agents to improve the efficacy of harnessing immune system.
• Still, we don't know the exact biomarker for these IO agents in gastric cancer. Not all patients get the benefit with these agents.

3. The importance of tumor microenvironment

• From the immunotherapy point of view, the tumor microenvironment (TME) should be considered for the successful immunotherapy.
• In TME, many components working for antitumor immunity and intratumoral immunosuppression exist. (Pitt JM et al. 2016)
• The most crucial and direct control of tumor cells is performed by CD4+ T helper cell and CD8+ cytotoxic T lymphocyte (CTL). Th1 response, characterized by T cell production of IFN-ɣ, TNF-α, IL-2 are considered to be the essential subset for tumor rejection. However, Th1 response also contributes to tumor escape via IFN-ɣ-mediated expression of the inhibitory checkpoint molecules PDL1 or via the selection of resistant clones through tumor immunoediting.
• Long-term exposure to tumor antigen induces Th1 cells and other T cells that lack the typical poly-functional phenotype and that express inhibitory receptors such as PDL1. LAG-3, and TIM-3.
• Other subsets of CD4+T cells inhibit antitumor immune responses. CD4+Tregs is the example. Tregs inhibit the antitumor activity of CTLs and NK cells either directly, or indirectly via APCs. In addition to Tregs, Th2 cells can also block Tcell-induced tumor rejection.
• TME can also directly impair intratumoral T cell proliferation, acting as another mechanism for tumor evasion of immune surveillance. IDO production within the TME is the example. IDO produced by myeloid cells and cancer cells catabolizes tryptophan to generate kynurenine, which together promotes the conversion of naïve T cells to Tregs,inhibition of Treg reprogramming to potentially anti-tumoral Th cells, and increases MDSC functions through upregulation of IL-6 expression.

4. The role of polarized macrophage in TME

• Macrophages are one of the major components of the TME, are recruited by chemokines such as M-CSF and chemokine C-C motif ligand 2, and are produced mainly be tumor cells (Wiktor-Jedrzejczak W, et al. 1996)
• Macrophages are dynamic cells that can express different functional programs in response to microenvironmental signals (Mantovani A, et al. 2004)
• Bacterial stimuli, IFN-ɣ and GM-CSF promote a proinflammatory M1-polarized phenotype, whereas M-CSF, IL-4, and IL-13 favor the generation of folate receptor b positive, IL-10 producing, immunosuppressive, M2-polarized macrophages. (Murray PJ, et al. 2011). M1 macrophages also amplify TH1 responses, providing a positive feedback loop in the antitumor response.
• Macrophages that infiltrate tumor tissues, also termed tumor-associated macrophages (TAMs), can be driven by tumor-derived and T-cell derived cytokines to acquire such a polarized phenotype, and have a key role in subversion of adaptive immunity and in inflammatory circuits that promote tumor growth and progression. (Mantovani A, et al. 2002)
• Fully polarized M1 and M2 macrophages are the extremes of a continuum of functional states; in contrast to this binary M1/M2 definition, there are several other distinct populations that share features of both types.( Ojalvo LS, et al. 2009)
• The M2-polarized macrophages promote tumor progression and metastasis by activating circuits that regulate tumor growth, adaptive immunity, stroma formation, and angiogenesis, and can be used as prognostic indicators. ( Balkwill F, et al. 2001)

5. The role of polarized macrophage in gastric cancer