Immune checkpoint inhibitors in renal cell carcinoma

The immune system has long been known to play a critical role in the body's defence against cancer, and there have been multiple attempts to harness it for therapeutic gain. Renal cancer was, historically, one of a small number of tumour types where immune manipulation had been shown to be effective. The current generation of immune checkpoint inhibitors are rapidly entering into routine clinical practice in the management of a number of tumour types, including renal cancer, where one drug, nivolumab, an anti-programmed death-1 (PD-1) monoclonal antibody (mAb), is licensed for patients who have progressed on prior systemic treatment. Ongoing trials aim to maximize the benefits that can be gained from this new class of drug by exploring optimal timing in the natural course of the disease as well as combinations with other checkpoint inhibitors and drugs from different classes

Evidence-Based Treatment Options in Recurrent and/or Metastatic Squamous Cell Carcinoma of the Head and Neck.

The major development of the past decade in the first-line treatment of recurrent and/or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN) was the introduction of cetuximab in combination with platinum plus 5-fluorouracil chemotherapy (CT), followed by maintenance cetuximab (the EXTREME regimen). This regimen is supported by a phase 3 randomized trial and subsequent observational studies, and it confers well-documented survival benefits, with median survival ranging between approximately 10 and 14 months, overall response rates between 36 and 44%, and disease control rates of over 80%. Furthermore, as indicated by patient-reported outcome measures, the addition of cetuximab to platinum-based CT leads to a significant reduction in pain and problems with social eating and speech. Conversely, until very recently, there has been a lack of evidence-based second-line treatment options, and the therapies that have been available have shown low response rates and poor survival outcomes. Presently, a promising new treatment option in R/M SCCHN has emerged: immune checkpoint inhibitors (ICIs), which have demonstrated favorable results in second-line clinical trials. Nivolumab and pembrolizumab are the first two ICIs that were approved by the US Food and Drug Administration. We note that the trials that showed benefit with ICIs included not only patients who previously received ≥1 platinum-based regimens for R/M SCCHN but also patients who experienced recurrence within 6 months after combined modality therapy with a platinum agent for locally advanced disease. In this review, we outline the available clinical and observational evidence for the EXTREME regimen and the initial results from clinical trials for ICIs in patients with R/M SCCHN. We propose that these treatment options can be integrated into a new continuum of care paradigm, with first-line EXTREME regimen followed by second-line ICIs. A number of ongoing clinical trials are comparing regimens with ICIs, alone and in combination with other ICIs or CT, with the EXTREME regimen for first-line treatment of R/M SCCHN. As we eagerly await the results of these trials, the EXTREME regimen remains the standard of care for the first-line treatment of R/M SCCHN

Immunotherapy in hepatocellular carcinoma: the complex interface between inflammation, fibrosis, and the immune response.

Hepatocellular carcinoma (HCC) is the third leading cause of cancer deaths worldwide and confers a poor prognosis. Beyond standard systemic therapy with multikinase inhibitors, recent studies demonstrate the potential for robust and durable responses from immune checkpoint inhibition in subsets of HCC patients across disease etiologies. The majority of HCC arises in the context of chronic inflammation and from within a fibrotic liver, with many cases associated with hepatitis virus infections, toxins, and fatty liver disease. Many patients also have concomitant cirrhosis which is associated with both local and systemic immune deficiency. Furthermore, the liver is an immunologic organ in itself, which may enhance or suppress the immune response to cancer arising within it. Here, we explore the immunobiology of the liver from its native state to chronic inflammation, fibrosis, cirrhosis and then to cancer, and summarize how this unique microenvironment may affect the response to immunotherapy

Human plasmacytoid dendritic cells and cutaneous melanoma

The prognosis of metastatic melanoma (MM) patients has remained poor for a long time. However, the recent introduction of effective target therapies (BRAF and MEK inhibitors for BRAFV600-mutated MM) and immunotherapies (anti-CTLA-4 and anti-PD-1) has significantly improved the survival of MM patients. Notably, all these responses are highly dependent on the fitness of the host immune system, including the innate compartment. Among immune cells involved in cancer immunity, properly activated plasmacytoid dendritic cells (pDCs) exert an important role, bridging the innate and adaptive immune responses and directly eliminating cancer cells. A distinctive feature of pDCs is the production of high amount of type I Interferon (I-IFN), through the Toll-like receptor (TLR) 7 and 9 signaling pathway activation. However, published data indicate that melanoma-associated escape mechanisms are in place to hijack pDC functions. We have recently reported that pDC recruitment is recurrent in the early phases of melanoma, but the entire pDC compartment collapses over melanoma progression. Here, we summarize recent advances on pDC biology and function within the context of melanoma immunity

A Phase II Basket Trial of Dual Anti-CTLA-4 and Anti-PD-1 Blockade in Rare Tumors (DART SWOG 1609) in Patients with Nonpancreatic Neuroendocrine Tumors.

PurposeImmune checkpoint blockade has improved outcomes across tumor types; little is known about the efficacy of these agents in rare tumors. We report the results of the (nonpancreatic) neuroendocrine neoplasm cohort of SWOG S1609 dual anti-CTLA-4 and anti-PD-1 blockade in rare tumors (DART).Patients and methodsWe performed a prospective, open-label, multicenter phase II clinical trial of ipilimumab plus nivolumab across multiple rare tumor cohorts, with the (nonpancreatic) neuroendocrine cohort reported here. Response assessment by grade was not prespecified. The primary endpoint was overall response rate [ORR; RECIST v1.1; complete response (CR) and partial response (PR)]; secondary endpoints included progression-free survival (PFS), overall survival (OS), stable disease >6 months, and toxicity.ResultsThirty-two eligible patients received therapy; 18 (56%) had high-grade disease. Most common primary sites were gastrointestinal (47%; N = 15) and lung (19%; N = 6). The overall ORR was 25% [95% confidence interval (CI) 13-64%; CR, 3%, N = 1; PR, 22%, N = 7]. Patients with high-grade neuroendocrine carcinoma had an ORR of 44% (8/18 patients) versus 0% in low/intermediate grade tumors (0/14 patients; P = 0.004). The 6-month PFS was 31% (95% CI, 19%-52%); median OS was 11 months (95% CI, 6-∞). The most common toxicities were hypothyroidism (31%), fatigue (28%), and nausea (28%), with alanine aminotransferase elevation (9%) as the most common grade 3/4 immune-related adverse event, and no grade 5 events.ConclusionsIpilimumab plus nivolumab demonstrated a 44% ORR in patients with nonpancreatic high-grade neuroendocrine carcinoma, with 0% ORR in low/intermediate grade disease

Excellent Response to Anti-PD1 therapy in a Patient with Hepatocellular Carcinoma: Case Report and Review of Literature

Hepatocellular carcinoma (HCC) is an aggressive cancer associated with high mortality worldwide. HCC develops in the setting of underlying cirrhosis due to chronic liver disease. Surgery is usually considered the treatment of choice for early disease; however, most patients have locally advanced or metastatic HCC at diagnosis in which case treatments are limited. Immune checkpoint blockade of programmed death receptor-1 (PD-1) pathway offers a potential treatment strategy based on the encouraging results of the phase I/II trial of nivolumab (Checkmate 040 trial). This has led to the off-label use of nivolumab after failure of treatment with sorafenib either due to intolerance or progression of disease. Although rare (<5%), clinical response to anti-PD-1 antibody may be preceded by "pseudoprogression" -- increase in the size and number of tumor lesions before actual tumor shrinkage. We report a case of pseudoprogression followed by an excellent response in an HCC patient treated with nivolumab and review the literature for ongoing trials of immune checkpoint blockade in HCC. The pseudoprogression in our case is supported by increase in both tumor size and alpha-fetoprotein after four treatments with nivolumab; however, regression of tumor size and normalization of alpha-fetoprotein occurred after subsequent treatments. To our knowledge, there are no reports of pseudoprogression in HCC although pseudoprogression has been well described in melanoma

Immunotherapy and radiation therapy for gastrointestinal malignancies: Hope or hype?

Immunotherapy represents the newest pillar in cancer care. Although there are increasing data showing the efficacy of immunotherapy there is a spectrum of response across unselected populations of cancer patients. In fact, response rates can be poor even among patients with immunogenic tumors for reasons that remain poorly understood. A promising clinical strategy to improve outcomes, which is supported by an abundance of preclinical data, is combining immunotherapy with radiation therapy. Here we review the existing evidence and future directions for combining immunotherapy and radiation therapy for patients with gastrointestinal cancers

Novosti u imunoterapiji melanoma

Melanoma is considered to be the most immunogenic malignant tumour. This fact is recognized for many years, and certain forms of immunotherapy have been used in melanoma therapy for a considerable time. Treatment options for patients with metastatic melanoma have changed dramatically in the past 5 years, with the FDA approval of eight new therapeutic agents (immunotherapies and targeted therapies). During this period, melanoma immunotherapy has transitioned from cytokine-based treatment to antibody-mediated blockade of the cytotoxic Tlymphocyteassociated antigen4 (CTLA4) and, recently, the programmed cell-death protein 1 (PD1) immune checkpoints. These changes in the treatment options have dramatically improved patient outcomes, with the median overall survival of patients with metastatic melanoma increasing from approximately 9 months before 2011 to at least 2 years, and probably longer. Various types of immunotherapy, like pembrolizumab, nivolumab, ipilimumab, combined therapy with nivolumab and ipilimumab, and T-VEC, have been established in recent years as the standard-of-care treatment for metastatic melanoma patients.Melanomi se smatraju najimunogenijim zloćudnim tumorima. Ova je činjenica prepoznata već niz godina, te se neki oblici imunoterapije već dugo primjenjuju u liječenju melanoma. Terapijske opcije za liječenje bolesnika s metastatskim melanomom dramatično su se promijenile u zadnjih pet godina, te je Američka agencija za lijekove (FDA) odobrila osam novih lijekova (imunoterapije i ciljane terapije). Tijekom ovog razdoblja, imunoterapija melanoma promijenila se iz terapije bazirane na citokinima u protutijelima posredovanu blokadu citotoksičnog T-limfocitnog antigena 4 (CTLA-4), a u zadnje vrijeme u protutijelima posredovanu inhibiciju imunoloških kontrolnih točaka, prvenstveno proteina programirane stanične smrti 1 (PD-1). Ove su promjene terapijskih opcija dramatično poboljšale ishod liječenja bolesnika, te se medijan ukupnog preživljenja kod bolesnika s metastatskim melanomom povisio s približno 9 mjeseci prije 2011. godine, na najmanje 2 godine, a vjerojatno i dulje. Različiti oblici imunoterapije, poput pembrolizumaba, nivolumaba, ipilimumaba, kombinirane terapije nivolumabom i ipilimumabom, te T-VEC, postali su zadnjih godina standardni oblici liječenja bolesnika s metastatskim melanomom