High numbers of CD8+ CTLs and low numbers of regulatory T(reg) cells in tumor microenvironments (TME) predicts prolonged survival of ovarian cancer (OvCa) patients and the clinical effectiveness of PD-1 blockers in other cancers. We observed strong synergy between TLR ligands, IFN? and COX2 blockers in specifically inducing the CTL-attracting chemokines, but suppressing Treg attractants in preclinical OvCa models. Combination of rintatolimod (TLR3-ligand), IFN? and celecoxib (chemokine-modulating regimen; CKM) promoted accumulation of tumor-specific CTLs in mouse OvCa TME, and synergized with PD-1 blockade in mice with PD-1 resistant ID8 tumors, resulting in long-term (>100 days) survival in 50% of the animals. We initiated a phase I/II trial (NCT02432378) to test if local (i.p.) rintatolimod/IFN? is safe and effective in guiding ?DC1 vaccine-induced CXCR3+/CCR5+ CTLs to OvCa TME. We observed good tolerability of i.p. CKM and local elevation of CD8, PD-1, PD-L1 and PD-L2. We also observed that CKM-attracted CTLs and NK cells induce two separate (PD-1/PD-L1- and COX2-dependent), pathways of ?secondary? immune suppression, providing rationale for their simultaneous targeting to achieve long-lasting therapeutic effects. We propose to:
Aim 1 : Determine the safety of i.p-administered CKM and its effectiveness in promoting local accumulation of CTLs in the TME of ?DC1-vaccinated OvCa patients. Patients on phase II of NCT02432378 will receive neoadjuvant chemotherapy and ?DC1 vaccination, with or without local (i.p.) CKM. We will evaluate the impact of i.p. CKM on the magnitude and duration of local CTL influx. We will obtain preliminary data on potential clinical impact of the CKM/?DC1-vaccine treatment on PFS and OS.
Aim 2 : Determine the mechanism of induction of ?secondary? suppression in human OvCa TME in response to immune attack. We will test the hypothesis that CKM preferentially attracts CTLs, NK & Th1 cells (vs. MDSCs & Tregs), but that IFN?/TNF?-production by these effector cells triggers two independent pathways of ?secondary? suppression, mediated by PD-1/PD-L1/PD-L2 system and COX2/PGE2-system.
Aim 3 : Determine whether simultaneous targeting of PD-1 and COX2 results in sustained therapeutic effects of ?DC1 vaccines. We will test if ?DC1/CKM-activated CTLs activated PD-1/PD-L1 and COX2/PGE2- pathways in OvCa-bearing mice and if their complementary targeting results in therapeutic synergy. Guided by these results, we will finalize the design and will test if ?DC1[tumor]/(CKM combined with PD-1 blockade will induce objective clinical responses (iRECIST) in patients with unresectable OvCa. Programmatic Role: The unique role of Project 2 is to evaluate the longitudinal effects of locally-administered CKM, interplay between vaccination, CKM and PD-1 blockade, and the roles of the PD-1/PD-L1/PD-L2 system vs. COX2/PGE2 systems, as complementary mediators of ?secondary suppression? in TME.
We propose to perform phase II component of the clinical trial (NCT02432378) to test if local chemokine modulating regimen (CKM) involving (i.p.) rintatolimod and IFN? is effective in guiding the ?DC1 vaccine-induced CTLs to tumor tissues of patients with resectable ovarian cancer. We will evaluate COX2/PGE2 and PD-1/PD- L1/PD-L2 systems, as two complementary pathways of ?secondary? suppression mobilized in OvCa TME in response to immune attack, and test and if the elimination of both these systems will result in therapeutic synergy in mice. Guided by the results of these studies, we will finalize the design and perform a trial to test if the combined treatment with ?DC1 vaccines, CKM and PD-1 blockade, induces clinical responses in patients with unresectable OvCa.
