Concurrent PD-1 Research Articles

Concurrent PD-1 Blockade Negates the Effects of OX40 Agonist Antibody in Combination Immunotherapy through Inducing T-cell Apoptosis.

Combination therapies that depend on checkpoint inhibitor antibodies (Abs) such as for PD-1 or its ligand (PD-L1) together with immune stimulatory agonist Abs like anti-OX40 are being tested in the clinic to achieve improved antitumor effects. Here, we studied the potential therapeutic and immune effects of one such combination: Ab to PD-1 with agonist Ab to OX40/vaccine. We tested the antitumor effects of different treatment sequencing of this combination. We report that simultaneous addition of anti-PD-1 to anti-OX40 negated the antitumor effects of OX40 Ab. Antigen-specific CD8+ T-cell infiltration into the tumor was diminished, the resultant antitumor response weakened, and survival reduced. Although we observed an increase in IFNγ-producing E7-specifc CD8+ T cells in the spleens of mice treated with the combination of PD-1 blockade with anti-OX40/vaccine, these cells underwent apoptosis both in the periphery and the tumor. These results indicate that anti-PD-1 added at the initiation of therapy exhibits a detrimental effect on the positive outcome of anti-OX40 agonist Ab. These findings have important implications on the design of combination immunotherapy for cancer, demonstrating the need to test treatment combination and sequencing before moving to the clinic. Cancer Immunol Res; 5(9); 755-66. ©2017 AACR.

Concurrent OX40 and CD30 Ligand Blockade Abrogates the CD4-Driven Autoimmunity Associated with CTLA4 and PD1 Blockade while Preserving Excellent Anti-CD8 Tumor Immunity.

Although strategies that block FOXP3-dependent regulatory T cell function (CTLA4 blockade) and the inhibitory receptor PD1 have shown great promise in promoting antitumor immune responses in humans, their widespread implementation for cancer immunotherapy has been hampered by significant off-target autoimmune side effects that can be lethal. Our work has shown that absence of OX40 and CD30 costimulatory signals prevents CD4 T cell–driven autoimmunity in Foxp3-deficient mice, suggesting a novel way to block these side effects. In this study, we show that excellent antitumor CD8 T cell responses can be achieved in Foxp3KO mice deficient in OX40 and CD30 signals, particularly in the presence of concurrent PD1 blockade. Furthermore, excellent antitumor immune responses can also be achieved using combinations of Abs that block CTLA4, PD1, OX40, and CD30 ligands, without CD4 T cell–driven autoimmunity. By dissociating autoimmune side effects from anticancer immune responses, this potentially shifts this antitumor approach to patients with far less advanced disease.

Abstract CT102: Rates and impact of combination immunotherapy with tumor treating fields in a glioma cohort

Abstract Tumor-treating fields (TTF) are approved for use in patients with glioblastomas at recurrence (2011) or adjuvant setting (2016) due to survival benefit in various trials. Since 12/2012, 46 patients were treated with TTF for de novo or recurrent gliomas at Columbia University. Rates and outcomes of combination with immunotherapy were analyzed, given the recent preclinical data of synergism between TTF and PD1 targeted therapy. The impact of compliance was also analyzed in multivariable analyses in this retrospective cohort. Of 44 treated patients, 18 (41%) were women and 2 (5%), 4 (9%) and 36 (86%) had WHO grade II, III and IV gliomas. Median age at diagnosis was 56 (23-84) years. TTF was used at recurrence in 38 (86%), with a median of 2 (0-4) prior recurrences. Prior therapies included bevacizumab (22, 50%), surgery [25/44 (57%) gross total], radiation and temozolomide. Median TTF therapy duration was 1.8 (0.1-20.3) months. Only 2 (5%) experienced skin toxicity requiring interruptions. Compliance goal of 75% was met by 11/44 (25%) glioma patients. Concurrent systemic therapy was used in 35 (80%), including temozolomide (12, 27%), nitrosourea (2, 5%), bevacizumab (17, 39%), immunotherapy (26, 59%) or other (5, 11%). Objective response rate (ORR) based on RANO was noted in 25/42 (60%) of all gliomas and 21/38 (55%) of glioblastomas, At interim follow-up, progression free (PFS) and overall (OS) survival were 2.7 and 6.9 months, respectively. PFS was significantly increased among glioblastoma patients treated with concurrent immunotherapy (PFS: 3.3 vs. 1.95, p=0.0364). Long-term follow-up PFS and OS will be re-analyzed, along with the potential confounding impact of compliance rates. TTF improves survival for patients with glioblastomas. Immunotherapy shows promise for various tumor histologies. The possible synergism between these modalities in preclinical studies and this retrospective glioma series warrants further study in randomized controlled gliomas trials. We propose a single-arm phase II trial of concurrent PD1 inhibitor and TTF for patients with bevacizumab-naïve glioblastoma at second or third recurrence. OS is the primary endpoint; secondary endpoints include PFS, ORR, predictive value of PDL1 expression, and impact of compliance. Results from the EF-14 trial will serve as a historical control. Citation Format: Yazmin Odia, Jessica Schulte, Fabio Iwamoto. Rates and impact of combination immunotherapy with tumor treating fields in a glioma cohort [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT102. doi:10.1158/1538-7445.AM2017-CT102

PD-1 blockade reverts motility arrest of transferred tumor-infiltrating CD8+ T cells in adoptive cell transfer immunotherapy (TUM7P.1014)

Abstract Adoptive cell transfer (ACT) immunotherapy can result in complete responses in the treatment of metastatic solid cancers, however the majority of patients eventually progress. Although many immune regulatory programs are context-dependent, the in vivo behavior of adoptively-transferred CD8+ T cells over time remains unknown. Using the Pmel-1 model, we performed intravital microscopy of subcutaneous tumors in mice to visualize the in vivo motility of transferred tumor-specific CD8+ T cells. This revealed that CD8+ T cell motility arrest increased over time after adoptive transfer. By ex vivo analyses, behavioral change coincided with a reduction in IFN-γ production and glucose uptake. As the transferred cells strongly expressed PD-1, we treated mice with both ACT and anti-PD-1 blocking antibody to determine the effect of immune checkpoint blockade on cellular motility. In mice treated with anti-PD-1 blocking antibody, transferred intratumoral CD8+ T cell motility arrest diminished, as compared with controls. This corresponded with an increase in CD8+ T cell glucose uptake. These data demonstrate that intratumoral CD8+ T cell behavior in ACT is dynamic and that greater motility is associated with increased functionality and bioenergetic demand. Furthermore, concurrent PD-1 blockade exerts a cell-intrinsic effect on transferred CD8+ T cells suggesting synergy between ACT and anti-PD-1 immunotherapy and the potential for their combinatorial use in the treatment of cancer