Programmed Death-ligand 1 Antibody Research Articles

Programmed death-ligand 1 (PD-L1) expression in small bowel adenocarcinomas (SBA).

3619 Background: SBAs are rare, resulting in a paucity of data on effective treatments. Highly active immune surveillance within all parts of the intestine may explain the rarity. In such an environment, tumor cells may express PD-L1 to inhibit immune-mediated cytotoxicity. We hypothesized that SBAs would have a high prevalence of PD-L1 IHC positive cells, which could be a marker for future immunotherapeutic efficacy. Methods: Forty-five archived SBA primary tumor samples were selected for IHC staining with the PD-L1 (anti-B7-H1 clone 5H1) antibody. Patient records were reviewed for clinical data outcomes including overall survival (OS), gender, primary site, and known microsatellite instability (MSI) status. Results: By site, we examined 25 (56%) duodenal, 14 (31%) jejunal, and five (11%) ileal tumors. 53% of tumors (24/45) demonstrated strong PD-L1 staining, with 4/45 (9%) in a cellular pattern and 21/45 (47%) in the intratumoral stroma, morphologically consisting of a mononuclear cell infiltration. Stratified by disease location, 11/25 (44%) of the duodenal tumors (9/11 stromal pattern, 1/11 cellular pattern, 1/11 positive for both), 9/14 (64%) of the jejunal tumors (8/9 stromal, 1/9 cellular), and 3/5 (60%) of the ileal tumors (2/3 stromal, 1/3 cellular) are PD-L1 positive by IHC. One site-unclassified tumor had positive stromal staining. An unadjusted survival analysis shows that PD-L1 staining within tumor cells is associated with poorer median OS (10 months vs. 5.5 years, p = 0.0009 by Log-Rank). Stromal PD-L1 staining does not exhibit a statistically significant difference in OS (median 66.9 months, vs 34.5 months p = 0.51). Of five tumors known to be MSI-H, 1/5 (20%, stromal pattern) has concomitant PD-L1 expression. Conclusions: To our knowledge, this is the first report of PD-L1 expression in SBA, with 53% staining positive. Given reported activity of anti-PD1 therapy in gastric cancer and MSI-H colon cancer, this indicates a potential role for immunotherapy in SBA. Those expressing PD-L1 intracellularly may have worse outcomes. Further studies to address prognostic and therapeutic implications PD-L1 expression are indicated.

44IN - Immunotherapy: Myth or Reality?

ABSTRACT An improved understanding of kidney cancer (KC) tumor biology has led to major advancements in the treatment of patients with metastatic disease. While agents that target the VEGF and mTOR pathways prolong survival, resistance develops for most patients within the first year of therapy. Agents that lead to durable remissions are of urgent need to patients living with this disease. For two decades, the clinical experience with high-dose bolus IL-2 has served as proof of principle that immunotherapy can produce durable responses in a small percentage of KC patients. Basic and translational investigation to elucidate the molecular mechanisms that govern the interaction between a tumor and its host immune response has helped to explain why immunotherapies too often fail to achieve satisfactory results. In KC, obstacles to effective immunotherapy may include the physiological down-modulation of the immune response through the expression of programmed death ligand-1 (PD-L1) on tumor cells and cytotoxic T-lymphocyte antigen-4 (CTLA-4) on activated T cells, which serve to restrict the cytolytic function of tumor-infiltrating T lymphocytes, the proliferation of regulatory (CD4+ CD25+) T cells (T-regs) in response to nonspecific cytokine administration, and the immunosuppressive effects of elevated circulating VEGF levels and myeloid-derived suppressor cells (MDSC). These insights have encouraged investigators to pursue agents that block T-cell regulation (e.g., PD-1 and CTLA-4 antibodies), inhibit tumor-induced immunosuppression (e.g. PD-L1 antibody) and more specifically activate T-cells (eg, CD-137 antibody, IL-21), and dendritic cells (e.g. AGS-003). Several of these approaches have shown encouraging efficacy in early trials both as single agents and in combination with standard therapies. However, for “targeted immunotherapy” to reach its full potential, significant work will need to be done to improve patient selection by refining proposed predictive biomarkers and overcome resistance mechanisms through the development of combination regimens. Disclosure: D.F. McDermott: BMS, Merck, Genentech - Scientific Advosry Board Partiicpation, compensated.

Recent Advances of Immunotherapy in Lung Cancer: Anti-Programmed Cell Death-1/Programmed Death Ligand-1 Antibodies

SUMMARY: Encouraging data from the clinical trials of inhibiting programmed cell death-1 (PD-1)/programmed death-ligand (PD-L) pathway in recent years suggests improvement in the efficiency of immunotherapy in lung cancer. The interaction between PD-1 and its ligands, PD-L1 and PD-L2 as the second signal of the activation of T cells leads to the downregulation of T-cell responses and inhibit cytokine production. Blocking the PD-1/PD-L pathway can enhance antitumor immunity. Phase I clinical trials of anti-PD-1 or PD-L1 monoclonal antibodies showed promising safety and durable clinical activity in non-small-cell lung cancer. Currently, a lot of clinical trials of anti-PD-1/PD-L pathway monotherapy or combination therapy are ongoing. This review will focus on the mechanism of action of PD-1/PD-L pathway in antitumor immunity, in addition to the clinical activity and toxicity of anti-PD-1/PD-L1 monoclonal antibodies.

Abstract P2-10-02: PD-L1 protein expression is a prognostic biomarker in breast cancer

Abstract BACKGROUND: Programmed death ligand 1 (PD-L1) and its receptor, PD1, are involved in limiting immune response. In the context of cancer, tumor cells expressing PD-L1 can suppress the immune response of PD1-expressing tumor infiltrating lymphocytes (TILs). Disruption of this pathway with antibodies to either the ligand or the receptor has shown promise in the treatment of non small cell lung cancer, melanoma and renal cell cancer. Here we investigate the pathway in breast cancer. METHODS: PD-L1 protein expression was assessed on two Yale TMA breast cancer cohorts with two-fold redundancy by quantitative immunofluorescence (QIF) using AQUA technology. Cohort 1 (YTMA201) consists of 400 patients with has extensive follow-up and adjuvant treatment information. Cohort 2 (YTMA128) consists of 245 patients with limited follow-up and no treatment information. The PD-L1 antibody (Lieping Chen, clone 5H1) has been previously validated for specificity and reproducibility using transfected cell models. TILs were assessed by a pathologist for each cohort using a score from 0-3 based on the amount of TILs within the spot. AQUA scores for PD-L1 were used as a continuous variable and also cut at the median for outcome analysis. RESULTS: PD-L1 protein is positively correlated with TILs (p<0.0001 on cohort 1 and p = 0.0072 on cohort 2) and inversely correlated with estrogen receptor status (p<0.0001 on cohort 1 and p = 0.0188 on cohort 2) on both breast cancer cohorts examined (total n = 594). On cohort 1, PD-L1 protein expression is a marker of good prognosis as a continuous variable (p = 0.0271) as well as when cut at the median (p = 0.0151), particularly in the estrogen receptor positive subset of patients. CONCLUSIONS: PD-L1 expression in breast cancer is positively associated with TILs and inversely associated with estrogen receptor status on two independent breast cancer cohorts. PD-L1 protein expression shows prognostic value in breast cancer patients, particularly the ER positive subset of patients. Further assessment of PD-1 axis marker expression may be valuable as the associated therapeutics are being tested in breast cancer patients. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-10-02.

Abstract LB-288: A phase I study of MPDL3280A, an engineered PD-L1 antibody in patients with locally advanced or metastatic tumors.

Abstract Background: Programmed Death-Ligand 1 (PD-L1) is the predominant ligand that binds Programmed Death-1 (PD-1), an inhibitory receptor expressed on T cells following T-cell activation. PD-L1 is highly expressed in many human tumors and elevated expression is often associated with a worse prognosis. PD-L1 exerts an immune suppressive signal through binding to PD-1 and B7.1, and tumor expression of PD-L1 can mediate tumor immune evasion. Therefore, inhibition of PD-L1 binding represents an attractive strategy to reinvigorate tumor-specific T-cell immunity. MPDL3280A is a human monoclonal antibody engineered to optimize efficacy and safety through a modification in the Fc region of the antibody. MPDL3280A targets PD-L1, inhibiting interaction with its receptors that include PD-1 and B7.1. In preclinical models, inhibition of PD-L1 can lead to durable antitumor activity. Methods: A phase I, multicenter, open-label study was conducted to evaluate the safety, pharmacokinetics (PK), and antitumor activity of MPDL3280A administered intravenously every 3 weeks (q3w) in pts with locally advanced or metastatic solid tumors. The study includes 3+3 dose-escalation cohorts with a 21-day window to evaluate dose-limiting toxicity (DLT). Results: As of September 14, 2012, results from the dose escalation include 30 patients (pts) (median age 66 years, range 39-80 years), all PS 0-1, with a median of 2 (range 1-3) prior treatments, received a median of 5.5 doses (range 2-16) of MPDL3280A in 8 dose-escalation cohorts (0.01-20 mg/kg). No DLTs or [Grade (G) ≥4 adverse events (AEs) attributed to MPDL3280A] have been reported; related G3 AEs were limited to rash in 1 pt. Pneumonitis was not observed in any of the patients in the dose-escalation cohorts. MPDL3280A exposure increased with dose; furthermore, PK was linear at doses ≥1 mg/kg q3w and consistent with that expected for an IgG1 in humans. RECIST-based responses were observed in a variety of different tumor types with ongoing responses in all responding patients. Conclusions: MPDL3280A was well tolerated with an acceptable safety and efficacy profile in pts with a variety of advanced tumors. PK supports dosing intervals that include q2wk or q3wk administration. An expansion phase in numerous tumor types with biomarker assessments is ongoing. Citation Format: Michael S. Gordon, Omid Hamid, John Powderly, Maria Anderson, Gregg Fine, Ahmad Mokatrin, Marcin Kowanetz, Leabman Maya, Bryan A. Irving, Daniel S. Chen, F Stephen Hodi. A phase I study of MPDL3280A, an engineered PD-L1 antibody in patients with locally advanced or metastatic tumors. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-288. doi:10.1158/1538-7445.AM2013-LB-288