Adi Diab’s research while affiliated with University of Texas MD Anderson Cancer Center and other places

There is a critical need for effective treatments for leptomeningeal disease (LMD). Here, we report the interim analysis results of an ongoing single-arm, first-in-human phase 1/1b study of concurrent intrathecal (IT) and intravenous (IV) nivolumab in patients with melanoma and LMD. The primary endpoints are determination of safety and the recommended IT nivolumab dose. The secondary endpoint is overall survival (OS). Patients are treated with IT nivolumab alone in cycle 1 and IV nivolumab is included in subsequent cycles. We treated 25 patients with metastatic melanoma using 5, 10, 20 and 50 mg of IT nivolumab. There were no dose-limiting toxicities at any dose level. The recommended IT dose of nivolumab is 50 mg (with IV nivolumab 240 mg) every 2 weeks. Median OS was 4.9 months, with 44% and 26% OS rates at 26 and 52 weeks, respectively. These initial results suggest that concurrent IT and IV nivolumab is safe and feasible with potential efficacy in patients with melanoma LMD, including in patients who had previously received anti-PD1 therapy. Accrual to the study continues, including in patients with lung cancer. ClinicalTrials.gov registration: NCT03025256.

Purpose: Tilsotolimod is an investigational synthetic Toll-like receptor 9 (TLR9) agonist that has demonstrated anti-tumor activity in preclinical models. The ILLUMINATE-101 phase 1 study explored the safety, dose, efficacy, and immune effects of intra-tumoral (it) tilsotolimod monotherapy in multiple solid tumors. Methods: Patients with a diagnosis of refractory cancer not amenable to curative therapies received tilsotolimod in doses escalating from 8 to 32 mg into a single lesion at weeks 1, 2, 3, 5, 8, and 11. Additional patients with advanced malignant melanoma (MM) were enrolled into an expansion cohort at the 8 mg dose. Objectives included characterizing the safety, establishing the dose, efficacy, and immunological assessment. Blood samples and tumor biopsies of injected and non-injected lesions were obtained at baseline and 24 hours post treatment for immune analyses. Results: 38 & 16 patients were enrolled into the dose escalation and melanoma expansion cohorts, respectively. Deep visceral injections were conducted in 91% of patients. No dose-limiting toxicities (DLTs) or Grade 4 treatment-related adverse events were observed. Biopsies 24 hours after treatment demonstrated an increased IFN pathway signature and dendritic cell maturation. Immunologic profiling revealed upregulation of IFN-signaling genes and modulation of genes for checkpoint proteins. In the dose escalation cohort, 12 (34%) of 35 evaluable patients achieved a best overall response rate (ORR) of stable disease (SD) while 3 (19%) of 16 evaluable patients in the melanoma cohort achieved stable disease. Conclusion: Overall, tilsotolimod monotherapy was generally well tolerated and induced rapid, robust alterations in the tumor microenvironment.

Background Patients with autoimmune disorders and cancer are at risk of developing immune-related adverse events (irAEs) and increasing flares of their underlying disease with immune checkpoint inhibitors (ICI) and harms and benefits must be weighed. Objectives We conducted an assessment of learning needs. Methods We interviewed 19 patients who had received an ICI and 20 physicians who provide care for these patients. We asked what do cancer patients with pre-existing autoimmune diseases need to know in order to make an informed decision about whether to receive an ICI. Results Fifty-three percent of the patients were female, median age was 62.9 (±10.9). They had rheumatoid arthritis (47.4%), psoriasis (26.3%), Crohn’s disease (10.5%), ankylosing spondylitis (5.3%), systemic lupus erythematosus (5.3%), or ulcerative colitis (5.3%). Half of the patients (52.6%) had a demonstrable disease activity of the autoimmune disease at the time of making the decision on whether to start ICI. Most (84%) of the patients had melanoma, and at the time of the interview 68.4% had completed or discontinued the ICI. Physicians were melanoma oncologists (30%), thoracic-head & neck medical oncologists (25%), rheumatologists (20%), gastroenterologists (10%), and dermatologists (15%) who treat patients with irAEs. Sixty percent were female. Key points mentioned by patients and physicians included information on probability of irAEs and flares of the autoimmune condition with discussion about severity, benefits of ICI, ICI mechanism of action in the context of the autoimmune disease, and management for flare-ups. Key topics raised only by patients included possible reasons for stopping or modifying treatment (for cancer or autoimmune disease), when to contact the provider, possibility of autoimmune disease progression or organ damage, sharing information with other providers, and lifestyle changes that can be done to help. Conclusion Although patients and physicians listed common learning points, patients also considered specific needs to increase their self-care. The information derived from this study will be used to develop a decision support tool. Disclosure of Interests None declared

Hepatocellular carcinoma (HCC) represents the second most common cause of cancer-related deaths and accounts for over eighty percent of primary liver cancers worldwide. Surgical resection and radiofrequency ablation in small tumors are included in the treatment options for HCC patients with good liver function profiles. According to the Milan Criteria, only a small portion of HCC patients are eligible for liver transplantation due to advanced-stage disease and large tumor size preventing/delaying organ allocation. Recently, the use of anti-programmed cell death protein 1 and programmed cell death ligand 1 (PD-1 and PD-L1) checkpoint inhibitors in the treatment of cancers have evolved rapidly and these therapies have been approved for the treatment of HCC. Immune checkpoint inhibitors have resulted in good clinical outcomes in pre-and post-transplant HCC patients, although, some reports showed that certain recipients may face rejection and graft loss. In this review, we aim to illustrate and summarize the utilization of immune checkpoint inhibitor therapies in pre-and post-liver transplants for HCC patients and discuss the assessment of immune checkpoint inhibitor regulators that might determine liver transplant outcomes.

Finding biomarkers for predicting anti-tumor responses and immune-related adverse events (irAEs) with immune checkpoint therapy remains a challenge. Lozano et al. have developed a composite biomarker score that includes the frequency of effector-memory CD4 T cells and TCR clonality of CD4 T cells in peripheral blood as a potentially predictive biomarker of irAEs.

Many patients with advanced melanoma are resistant to immune checkpoint inhibition. In the ILLUMINATE-204 phase I/II trial, we assessed intratumoral tilsotolimod, an investigational Toll-like receptor 9 agonist, with systemic ipilimumab in patients with anti–PD-1– resistant advanced melanoma. In all patients, 48.4% experienced grade 3/4 treatment-emergent adverse events. The overall response rate at the recommended phase II dose of 8 mg was 22.4%, and an additional 49% of patients had stable disease. Responses in noninjected lesions and in patients expected to be resistant to ipilimumab monotherapy were observed. Rapid induction of a local IFNα gene signature, dendritic cell maturation and enhanced markers of antigen presentation, and T-cell clonal expansion correlated with clinical response. A phase III clinical trial with this combination (NCT03445533) is ongoing. Significance Despite recent developments in advanced melanoma therapies, most patients do not experience durable responses. Intratumoral tilsotolimod injection elicits a rapid, local type 1 IFN response and, in combination with ipilimumab, activates T cells to promote clinical activity, including in distant lesions and patients not expected to respond to ipilimumab alone. This article is highlighted in the In This Issue feature, p. 1861

Cancer treatment has been fully transformed with the development of cancer immunotherapies. The progress in the understanding of the immune system has led to the development of monoclonal antibodies targeted against regulatory immune checkpoints, which control T-cell activation. These therapies produce an antitumor response characterized by constant surveillance, specificity against tumor antigen, and long-lasting memory to protect against tumor relapse. In this chapter, we will discuss seven Food and Drug Administration-approved immune checkpoint inhibitors for the treatment of various malignancies, targeting two main signaling pathways, cytotoxic T-lymphocyte antigen 4 and programmed cell death 1/programmed cell death ligand-1.