The 2017 Clinical Immuno-Oncology Symposium achieved a successful first year, in which 950 physicians, researchers, translation-oriented scientists, and others gathered to learn about state-of-the-art developments in the science and application of immuno-oncology. “With this meeting, our goal was to help researchers and clinicians alike discuss new therapies and present and support the novel research driving this field forward,” said Mary L. (Nora) Disis, MD, of the University of Washington and chair of the Planning Committee. “We can’t wait to follow the success of this meeting in years to come.”
Read on for a snapshot of the top research presented during the meeting.
Immune Checkpoint Targets
A wealth of research underscores the potential utility of targeting immune checkpoint pathways. However, it is clear that inhibiting just one immune checkpoint often is insufficient to generate a durable tumor response in many individuals. Two talks investigated potential avenues for combined immune checkpoint inhibition.
- Combined PD-1 and CTLA-4 inhibition in squamous cell carcinoma of the head and neck may help boost treatment responses, according to exploratory analyses of circulating immune cells obtained from the participants of CheckMate 141 (Abstract 5). These findings suggest that the response to nivolumab treatment may be associated with a higher frequency of circulating CD8+ T cells at baseline in tandem with a decrease in CTLA-4+ CD8+ effector T cells during treatment.
- Preclinical research has identified CD38 as a novel immune checkpoint protein—one that works by inhibiting CD8+ T-cell function and that overcomes resistance to inhibition of the PD-1/PD-L1 axis in lung cancer models (Abstract 79). Although still conjecture, the findings suggest that targeting CD38 may enable more patients with advanced non–small cell lung cancer (NSCLC) to benefit from PD-L1/PD-1 blockade.
Advances in the Development and Application of Immunotherapy
The 2017 Clinical Immuno-Oncology Symposium included 950 attendees.
- Modeling analyses estimate that 21% to 25% of patients with PD-L1–positive advanced NSCLC who previously received platinum-containing chemotherapy will survive more than 5 years after treatment with pembrolizumab, compared with only 3% to 4% of patients treated with docetaxel (Abstract 77).
- The investigational agent plinabulin, which may exert myriad effects in the tumor microenvironment, shows potential for improving overall survival (OS) when added to docetaxel in previously treated patients with locally advanced or metastatic NSCLC. Patients with measurable disease appeared to benefit most from the addition of plinabulin to docetaxel; they achieved a 4.6-month improvement in median OS and a nearly 1-year improvement in the duration of response (Abstract 139).
- A small study of 22 patients with stage III/IV melanoma demonstrates that intratumoral administration of plasmid interleukin-12 (IL-12) in combination with pembrolizumab drives a safe but powerful systemic immune response, largely by increasing the number of effector CD8+ tumor-infiltrating lymphocytes that flood melanoma lesions (Abstract 78). The 48% objective response rate is particularly striking, given that all patients enrolled in the study had fewer than 25% PD-1hiCTLA-4+ CD8+ tumor-infiltrating lymphocytes—a value that normally signals a lack of response to anti–PD-1 therapy in the absence of plasmid IL-12.
- Emerging data from a small clinical trial of 74 patients with metastatic melanoma suggests that checkpoint blockade may greatly blunt the response to subsequent adoptive cell therapy of autologous tumor-infiltrating lymphocytes through mechanisms as yet unidentified (Abstract 138). Previous receipt of ipilimumab decreased the overall adoptive cell therapy response rate from 51% to 33% and the median OS from 24.6 months to 7.7 months compared with patients who were naïve to checkpoint inhibitors.
Prognostic and Predictive Markers of Response
Biomarkers hold the power to inform clinicians about the interplay between the immune system and cancer, sometimes offering insight into disease prognoses and sometimes signaling when a particular immunotherapy stands to offer benefit in selected patients. Several noteworthy studies focused on this theme.
- Tumors appear to release biologically active, soluble forms of PD-L1 (sPD-L1) into systemic circulation, which may contribute to poor clinical outcomes. Analyses in patients with metastatic melanoma showed that high levels of sPD-L1 at baseline appeared tied to an immunosuppressive phenotype (i.e., Th2 cell bias), decreased median OS (11.3 vs. 14.8 months for, respectively, sPD-L1 levels greater than vs. less than or equal to 0.293 ng/mL), and resistance to anti–PD-1 therapy (Abstract 4). Larger studies now are needed to establish the utility of sPD-L1 as a prognostic and possibly predictive biomarker.
- The specific bacteria living in the stomach appear tied somehow to the degree of response to certain immunotherapies in patients with metastatic melanoma (Abstract 2). The more diverse the organisms that comprise the gut microbiome, and the greater the abundance of Clostridia, particularly bacteria from the Ruminococcaceae family, the better the response to anti–PD-1 therapy, perhaps because of enhanced immunity.
- In an analysis of 153 patients with a variety of PD-L1–positive solid tumors, a high mutational load (≥ 102 mutations) and a gene expression profile indicative of an inflamed tumor microenvironment (e.g., T-cell infiltration, PD-L1/PD-L2 upregulation, interferon gamma expression) each independently predicted a favorable response to pembrolizumab (Abstract 1). Combination of these two biomarkers clearly correlated with a higher response rate (38% vs. 0%) and with longer progression-free survival (175 vs. 59 days) among representative patients compared with patients with a low mutational load and lack of an inflammatory gene expression profile.
- A long-term update of the ongoing APN 311-303 trial, in which 53 patients with high-risk relapsed/refractory neuroblastoma received long-term infusions of the anti-GD2 monoclonal antibody dinutuximab beta in conjunction with IL-2, revealed that polymorphisms in receptors on natural killer cells both influenced antibody-dependent cell-mediated cytotoxicity activity and correlated with patient survival (Abstract 111). Higher antibody-dependent cell-mediated cytotoxicity activity and superior survival were evident in patients who harbored genes for high-affinity versions of the Fcɣ receptors on natural killer cells that bind avidly to Fc on antibodies like dinutuximab beta or genes that reflect a specific stimulatory killer cell Ig-like receptor haplotype.
Insight Into the Tumor Microenvironment
The immunotherapy field has come to appreciate that the tumor microenvironment represents a pathologically active niche that influences both tumor evolution and the response to therapy. One study shed additional light on this topic.
- In-depth molecular analyses of T cells within the microenvironment suggest that metastatic melanoma is not a singular disease within an individual patient but, rather, is a collection of different lesions potentially subject to different local immune composition, regulation, and recognition (Abstract 3). This assessment is based on observations that the T cells within the melanoma microenvironment display a distinct phenotype and functional profile consistent with that of resident memory T cells, which differs markedly from the phenotype and functional profile of circulating T cells.
–Kara Nyberg, PhD