Faculty Bibliography

The identification of predictive biomarkers for the benefit of cancer immunotherapy is the holy grail of the burgeoning immunotherapy field. Recent work has shown that there are a core of concepts that establish the presence of an immune cell-infiltrate, an inflammatory signature of the tumor microenvironment, and the availability of target antigens defined by mutated neoantigens, as critical for the success of the checkpoint blockade. Genetic analyses have shown that resistance to PD-1 blockade, either innate or adaptive, may be due to existing or de novo mutations in signaling pathways critical for T-cell function in a modest proportion of cases. Major hurdles in the field that remain to be overcome are the difficulty of obtaining tumor biopsies for biomarker assessment, the heterogeneity of biomarker expression within tumors and within different tumors from the same patient, and the inducibility of some biomarkers by disease-related processes. Although assessment of peripheral blood or serum biomarkers would be ideal, few data suggest that they would reliably predict outcome with checkpoint blockade. Ultimately, some amalgamated biomarker that includes tumor and host factors will be required to predict which patients are likely to benefit from, or be resistant to, the effects of checkpoint inhibition.

Histone acetylation and the families of enzymes responsible for controlling these epigenetic marks have been implicated in regulating T-cell maturation and phenotype. Here, we demonstrate a previously undefined role of histone deacetylase 11 (HDAC11) in regulating T-cell effector functions. Using EGFP-HDAC11 transgenic reporter mice, we found that HDAC11 expression was lower in effector relative to naive and central memory T-cell populations, and activation of resting T-cells resulted in its decreased expression. Experiments using HDAC11 knockout (KO) mice revealed that T-cells from these mice displayed enhanced proliferation, pro-inflammatory cytokine production and effector molecule expression. Additionally, HDAC11KO T-cells had increased expression of Eomesodermin (Eomes) and TBX21 (Tbet), transcription factors previously shown to regulate inflammatory cytokine and effector molecule production. Conversely, overexpression of HDAC11 resulted in decreased expression of these genes. Chromatin immunoprecipitation showed the presence of HDAC11 at the Eomes and Tbet gene promoters in resting T-cells, where it rapidly disassociated following T-cell activation. In vivo, HDAC11KO T-cells were refractory to tolerance induction. HDAC11KO T-cells also mediated accelerated onset of acute graft-vs-host disease (GvHD) in a murine model, characterized by increased proliferation of T-cells and expression of IFNgamma, TNF and EOMES. Additionally, adoptive transfer of HDAC11KO T-cells resulted in significantly reduced tumor burden in a murine B-cell lymphoma model. Taken together, these data demonstrate a previously unknown role of HDAC11 as a negative epigenetic regulator of T-cell effector phenotype and function.

BACKGROUND: Despite unprecedented efficacy across multiple tumor types, immune checkpoint inhibitor therapy is associated with a unique and wide spectrum of immune-related adverse events (irAEs), including neurologic events ranging from mild headache to potentially life-threatening encephalitis. Here, we summarize neurologic irAEs associated with nivolumab and ipilimumab melanoma treatment, present cases of treatment-related encephalitis, and provide practical guidance on diagnosis and management. METHODS: We searched a Global Pharmacovigilance and Epidemiology database for neurologic irAEs reported over an 8-year period in patients with advanced melanoma receiving nivolumab with or without ipilimumab from 12 studies sponsored by Bristol-Myers Squibb. Serious neurologic irAEs were reviewed, and relationship to nivolumab or ipilimumab was assigned. RESULTS: In our search of 3,763 patients, 35 patients (0.93%) presented with 43 serious neurologic irAEs, including neuropathy (n = 22), noninfective meningitis (n = 5), encephalitis (n = 6), neuromuscular disorders (n = 3), and nonspecific adverse events (n = 7). Study drug was discontinued (n = 20), interrupted (n = 8), or unchanged (n = 7). Most neurologic irAEs resolved (26/35 patients; 75%). Overall, median time to onset was 45 days (range 1-170) and to resolution was 32 days (2-809+). Median time to onset of encephalitis was 55.5 days (range 18-297); four cases resolved and one was fatal. CONCLUSION: Both oncologists and neurologists need to be aware of signs and symptoms of serious but uncommon neurologic irAEs associated with checkpoint inhibitors. Prompt diagnosis and management using an established algorithm are critical to minimize serious complications from these neurologic irAEs. The Oncologist 2017;22:1-10Implications for Practice: With increasing use of checkpoint inhibitors in cancer, practicing oncologists need to be aware of the potential risk of neurologic immune-related adverse events and be able to provide prompt treatment of this uncommon, but potentially serious, class of adverse events. We summarize neurologic adverse events related to nivolumab alone or in combination with ipilimumab in patients with advanced melanoma from 12 studies and examine in depth 6 cases of encephalitis. We also provide input and guidance on the existing neurologic adverse events management algorithm for nivolumab and ipilimumab.

Purpose We conducted a retrospective analysis to assess the safety profile of nivolumab monotherapy in patients with advanced melanoma and describe the management of adverse events (AEs) using established safety guidelines. Patients and Methods Safety data were pooled from four studies, including two phase III trials, with patients who received nivolumab 3 mg/kg once every 2 weeks. We evaluated rate of treatment-related AEs, time to onset and resolution of select AEs (those with potential immunologic etiology), and impact of select AEs and suppressive immune-modulating agents (IMs) on antitumor efficacy. Results Among 576 patients, 71% (95% CI, 67% to 75%) experienced any-grade treatment-related AEs (most commonly fatigue [25%], pruritus [17%], diarrhea [13%], and rash [13%]), and 10% (95% CI, 8% to 13%) experienced grade 3 to 4 treatment-related AEs. No drug-related deaths were reported. Select AEs (occurring in 49% of patients) were most frequently skin related, GI, endocrine, and hepatic; grade 3 to 4 select AEs occurred in 4% of patients. Median time to onset of select AEs ranged from 5 weeks for skin to 15 weeks for renal AEs. Approximately 24% of patients received systemic IMs to manage select AEs, which in most cases resolved. Adjusting for number of doses, objective response rate (ORR) was significantly higher in patients who experienced treatment-related select AEs of any grade compared with those who did not. ORRs were similar in patients who did and patients who did not receive systemic IMs. Conclusion Treatment-related AEs with nivolumab monotherapy were primarily low grade, and most resolved with established safety guidelines. Use of IMs did not affect ORR, although treatment-related select AEs of any grade were associated with higher ORR, but no progression-free survival benefit.

In CheckMate 037, patients (pts; n = 405) with MEL who progressed on/after anti-CTLA-4 therapy (plus a BRAF inhibitor if BRAF V600 positive), were randomized 2:1 to NIVO 3 mg/kg IV Q2W or ICC (dacarbazine 1000 mg/m² Q3W or carboplatin AUC6+ paclitaxel 175 mg/m² Q3W). At the first analysis, objective response rate (ORR) for NIVO was 32% versus 11% for ICC. Here we report for the first time the co-primary endpoint of overall survival (OS), updated ORR, and the secondary endpoint of progression-free survival (PFS) assessed by independent radiology review. Of 272 pts randomized to NIVO and 133 to ICC, 99 and 77%, respectively, received study treatment. A larger proportion of NIVO versus ICC pts had brain metastases (20 versus 14%) and increased lactate dehydrogenase levels (52 versus 38%) at baseline. At ~2 years' minimum follow-up, ORR (27 versus 10%) and median duration of response (32 versus 13 months) were notably higher for NIVO versus ICC. Median OS was 16 versus 14 months (NIVO versus ICC) in all randomized pts (HR: 0.95 [95.5% CI: 0.73, 1.24]) and 16 versus 12 months (0.81 [95% CI: 0.59, 1.1]) in all treated pts censored at the start of subsequent PD-1/PD-L1 therapy, as 41% of ICC pts (11% NIVO) received subsequent anti-PD1 agents. Median PFS (NIVO versus ICC) was 3.1 versus 3.7 months (1.0 [95% CI: 0.78, 1.4]). Fewer grade 3/4 treatment-related AEs were observed in NIVO pts (14 versus 34%) and most NIVO-related AEs were low grade and manageable. In summary, in pts with MEL who progressed after IPI, NIVO demonstrated higher, more durable responses and did not show statistical significance in survival difference versus ICC. OS should be interpreted with caution because of the open-label study design and increased dropout rate prior to treatment initiation, subsequent ICC arm anti-PD-1 therapy, and increased proportion of pts with poor prognostic factors in the NIVO arm

Immune checkpoint blockade has revolutionized the care of patients (pts) with melanoma; however, treatment guidelines lack specific recommendations on the use of these agents for individual pt cases. We developed an interactive, online treatment (Tx) decision tool to assess whether expert Tx recommendations based on specific disease and pt characteristics would affect the planned Tx decisions of community practitioners. In January 2016, 5 experts provided Tx recommendations for 90 case variations based on key factors they considered important to guide Tx choice and then an online tool was developed to provide this guidance to clinicians. To use the tool, specific pt and disease characteristics along with the intended Tx for that pt were entered. Then Tx recommendations from 5 experts for that scenario were provided and users were prompted to indicate whether this online consultation would change their Tx plan. An analysis of 432 cases entered into the tool found variation between the intended use of immunotherapy among tool users versus Tx recommendations from the experts. For example, compared with the experts who all chose immune checkpoint blockade as frontline Tx for BRAF wild-type disease, 44% of tool users planned to use a different Tx or were unsure. For BRAF^V600-mutant disease with a good PS and normal LDH, all of the experts recommended frontline immunotherapy whereas 55% of users selected combination BRAF/MEK therapy for this scenario. In total, 59% of tool users whose planned Tx differed from the experts indicated that the expert recommendations from the tool would subsequently change their Tx plan. An analysis of specific first- and second-line agent and combination choice along with Tx variance in other case scenarios will be presented

Immunotherapy has moved to the center stage of cancer treatment with the recent success of trials in solid tumors with PD-1/PD-L1 axis blockade. Programmed death-1 or PD-1 is a checkpoint molecule on T cells that plays a vital role in limiting adaptive immune responses and preventing autoimmune and auto-inflammatory reactivity in the normal host. In cancer patients, PD-1 expression is very high on T cells in the tumor microenvironment, and PD-L1, its primary ligand, is variably expressed on tumor cells and antigen-presenting cells within tumors, providing a potent inhibitory influence within the tumor microenvironment. While PD-L1 expression on tumors is often regarded as a negative prognostic factor, it is clearly associated with a positive outcome for treatment with PD-1/PD-L1 blocking antibodies, and has been used to select patients for this therapy. Responses of long duration, a minority of patients with atypical responses in which progression may precede tumor shrinkage, and a pattern of autoimmune side effects often seen with this class of drugs characterize therapy with PD-1/PD-L1 blocking drugs. While excellent efficacy has been seen with a limited number of tumor types, most epithelial cancers do not show responses of long duration with these agents. In the current review, we will briefly summarize the scientific background data supporting the development of PD-1/PD-L1 blockade, and then describe the track record of these antibodies in multiple different histologies ranging from melanoma and lung cancer to less common tumor types as well as discuss biomarkers that may assist in patient selection.

The recent demonstration of the antitumor efficacy of checkpoint protein inhibition has resulted in the approval of blocking antibodies against the programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) pathway in multiple different histologic findings. Therapeutic successes with PD-1/PD-L1 antibodies in melanoma and lung cancer have been followed by approvals in bladder, renal, and head and neck cancers and Hodgkin lymphoma, with others undoubtedly to come. However, PD-1 is only one of many checkpoints and agonistic regulatory molecules expressed on T cells by which maintenance of the balance between costimulatory and coinhibitory signaling pathways is perturbed in cancer. The manipulation of many of these molecules in cancer patients might be associated with clinical benefit. The majority of the T-cell cosignaling receptors belong to either the immunoglobulin superfamily or the tumor necrosis factor receptor superfamily. A total of 29 immunoglobulin superfamily and 26 tumor necrosis factor receptor superfamily cosignaling receptors have been identified that are expressed on T cells, providing fertile ground for development of inhibitory or agonistic antibodies and small molecules as cancer therapeutics. In the current work, we focus on some of the most promising new checkpoints and agonistic or cosignaling molecules that are in early clinical development as single agents or in combinations with PD-1/PD-L1, cytotoxic T-lymphocyte-associated protein 4 blockade, or chemotherapy with an emphasis on those that have reached the clinic and on important targets that are in late preclinical development.