Block, Matthew S.

Objective Insulin-dependent diabetes can occur with immune checkpoint inhibitor (ICI) therapy. We aimed to characterize the frequency, natural history and potential predictors of ICI-induced diabetes. Research design and methods We reviewed 1444 patients treated with ICIs over 6 years at our cancer center, and from the 1163 patients who received programmed cell death protein 1 (PD-1) inhibitors, we identified 21 such cases, 12 of which developed new-onset insulin-dependent diabetes and 9 experienced worsening of pre-existing type 2 diabetes. Results ICI-induced diabetes occurred most frequently with pembrolizumab (2.2%) compared with nivolumab (1%) and ipilimumab (0%). The median age was 61 years, and body mass index was 31 kg/m2, which are both higher than expected for spontaneous type 1 diabetes. Other immune-related adverse events occurred in 62%, the most common being immune mediated thyroid disease. New-onset insulin-dependent diabetes developed after a median of four cycles or 5 months; 67% presented with diabetic ketoacidosis and 83% with low or undetectable C-peptide. Autoantibodies were elevated in 5/7 (71%) at the time of new-onset diabetes. Diabetes did not resolve during a median follow-up of 1 year. Conclusions PD-1 inhibitors can lead to insulin deficiency presenting as new-onset diabetes or worsening of pre-existing type 2 diabetes, with a frequency of 1.8 %. The underlying mechanism appears similar to spontaneous type 1 diabetes but there is a faster progression to severe insulin deficiency. Better characterization of ICI-induced diabetes will improve patient care and enhance our understanding of immune-mediated diabetes.

Abstract Despite unprecedented successes with immune checkpoint blockade in advanced cancers, these agents provide durable clinical benefit in only a subset of patients. In addition, the clinical management of patients receiving immune checkpoint blockade remains quite challenging due to the unpredictable and kinetically heterogeneous responses which can manifest as late responses, pseudoprogression, or hyperprogression in subsets of patients. The dynamics and heterogeneity of programmed cell death protein ligand 1 (PD-L1, aka B7-H1) expression confound its use as a predictive biomarker in cancer immunotherapy, but blood-based biomarkers have the potential to predict responders and detect mechanisms of resistance to immunotherapy. We previously reported that Bim (BH3-only protein) is a downstream signaling molecule of the PD-1 pathway, and that Bim levels in circulating tumor-reactive T-cells reflected patient responses to anti-PD-1 therapy in melanoma. We also discovered the existence of soluble PD-L1 (sPD-L1) in the plasma of cancer patients and showed a correlation of sPD-L1 with cancer stages in renal cell carcinoma and with prognosis in metastatic melanoma. Here we evaluated the frequency of tumor-reactive T cells with Bim expression along with effector memory profile and sPD-L1 as biomarkers of response in a new cohort of patients with metastatic melanoma and lung cancer undergoing anti-PD-1 therapy. We recruited 100 cancer patients treated with anti-PD-1 therapy who had peripheral blood collected at baseline and at each subsequent radiographic tumor evaluation. Frequencies of Bim+ and effector memory CD8+ T cells were measured by flow cytometry in gated tumor-reactive CD11a high PD1+ CD8+ T cells. We also measured levels of sPD-L1 in plasma at baseline and serially during treatment with ELISA. Baseline T cell markers and sPD-L1 levels and their percent changes in patients who had a radiographic response were compared to those who had progressive disease (PD). We found that patients with objective response after 4 cycles of anti-PD-1 therapy had higher frequency of Bim+ CD8+ T cells at baseline compared to patients with PD (mean 43% vs. 30%, P=0.0484). The frequencies of Bim+ T cells decreased significantly after the first 3 months of treatment in responders compared with progressors (mean -16% vs. + 40% P=0.0111). The frequency of effector memory CD8+ T cells also dramatically increased in responders in 3-6 months after anti-PD-1 therapy (mean 89% vs. 9.56%, p=0.002). High baseline sPD-L1 was associated with progression on anti-PD-1 therapy (mean 2.8 ng/mL vs. 0.7 ng/mL, p=0.07) or development of immune-related toxicities and the levels increased by 12 weeks in patients progressing on therapy. Conclusion: Measurements of T cell biomarkers (Bim and effector memory) and sPD-L1 levels provide a new noninvasive way to predict and monitor patient responses to anti-PD-1 monotherapy in melanoma and lung cancers. Note: This abstract was not presented at the conference. Citation Format: Roxana S. Dronca, Aaron Mansfield, Xin Liu, Susan Harrington, Elizabeth Enninga, Svetomir Markovic, Lisa Kottschade, Rob Mcwilliams, Matthew Block, Wendy Nevala, Michael Thompson, Haidong Dong. Blood-based T cell biomarkers and soluble PD-L1 predict responses and immune-related toxicity to PD-1 blockade in melanoma and lung cancer [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2017 Oct 1-4; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2018;6(9 Suppl):Abstract nr A38.

Some melanomas develop a striking avidity for lymphatic spread. In spite of multiple recurrences, patients can remain years without visceral metastasis. There is clearly a biologic reason for this lymphotrophic pattern of growth and dissemination, which we have yet to uncover. In‐transit metastases have widely diverse clinical presentations and can be a stubborn disease to cure. As a result, a host of treatments exist that should be tailored to the individual patient.

A vaccine that could expand melanoma-specific T cells might reduce the risk of recurrence of resected melanoma and could provide an alternative or adjunct to standard immunotherapy options. We tested the safety and immunogenicity of a vaccine coupling a melanoma-associated peptide with a xenogenic peptide (to promote epitope spreading) and/or resiquimod (to activate antigen-presenting cells). HLA-A2-positive patients with resected stage II, III, and IV melanoma were assigned to treatment on one of three schedules. All patients received three subcutaneous doses of the peptide MART-1a mixed with Montanide. In addition, patients on schedule 1 received the xenoantigen peptide Gag267–274, patients on schedule 2 received topical resiquimod, and patients on schedule 3 received both Gag267–274 and resiquimod. Blood samples were tested for the frequency of antigen-specific T cells by tetramer assay, as well as immune cell subtypes and plasma cytokine levels. Patients enrolled from October 2012 to December 2014, with 10 patients enrolling to each schedule. The most common adverse events were injection site reaction (26 patients) and fatigue (15 patients). Tetramer analysis revealed antigen-specific responses (defined as doubling of MART-1a-specific T cells from pretreatment to post-treatment) in 20, 60, and 40% of patients treated on schedules 1, 2, and 3, respectively. Vaccine treatment consisting of MART-1a peptide, Gag267–274, Montanide, and topical resiquimod was well-tolerated. The addition of the Gag267–274 xenoantigen was not associated with an increase in the response to MART-1a, whereas use of topical resiquimod was associated with a higher frequency of MART-1a-specific T-cell responses that did not meet statistical significance.