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Background: The risk of delayed autoimmunity occurring months or years after discontinuation of immunotherapy is frequently asserted in the literature. However, specific cases were rarely described until 2018, when a wave of reports surfaced. With expanding I-O indications in the adjuvant/neoadjuvant curative setting, growing numbers of patients will receive limited courses of immunotherapy before entering routine surveillance. In this context, under-recognition of DIRE could pose a growing clinical hazard., Methods: The aim of this study was to characterize DIRE through identification of existing reports of delayed post-treatment irAE in cancer patients treated with immunotherapy. We performed a PubMed literature review from 2008 through 2018 to determine the median data safety reporting window from existing I-O clinical trials, which we then applied to define the DIRE cutoff, and collated all qualifying reports over the same time span. DIRE was defined as new immune-related adverse events (irAE) manifesting ≥90 days after discontinuation of immunotherapy., Results: Median duration of I-O clinical trials data safety reporting was 90 days (82% ≤ 90 days). DIRE cutoff was thus set as ≥90 days post-immunotherapy. We identified 23 qualifying cases; 21 by literature review and 2 from our institution. Median off-treatment interval to DIRE was 6 months (range: 3 to 28). Median cumulative immunotherapy exposure was 4 doses (range: 3 to 42). Involvement included endocrine, neurologic, GI, pulmonary, cardiac, rheumatologic and dermatologic irAE., Conclusions: As immunotherapy indications expand into the curative setting, often with brief exposure and potentially sequenced with multimodality treatments, it will be necessary to recognize an emerging diagnostic complex, which we have termed delayed immune-related events (DIRE). Clinical vigilance has the potential to reduce morbidity from diagnostic delay, as irAE are generally manageable with prompt initiation of treatment - or from misdiagnosis - as misattribution can lead to unnecessary or harmful interventions as we describe. DIRE should therefore figure prominently in the differential diagnosis of patients presenting with illnesses of unclear etiology, irrespective of intervening treatments or interval post-immunotherapy, both of which can confound diagnosis. Increased recognition will rest on delineation of DIRE as a clinical diagnostic entity.

The concept of using immunotherapy to treat melanoma has existed for decades. The rationale comes from the knowledge that many patients with melanoma have endogenous immune responses against their tumor cells and clinically meaningful tumor regression can be achieved in a minority of patients using cytokines such as interleukin-2 and adoptive cellular therapy. In the last 5 years there has been a revolution in the clinical management of melanoma in large measure based on the development of antibodies that influence T cell regulatory pathways by overcoming checkpoint inhibition and providing co-stimulation, either of which results in significantly more effective immune-mediated tumor destruction. This review will describe the pre-clinical and clinical application of antagonistic antibodies targeting the T-cell checkpoints cytotoxic T-lymphocyte antigen 4 (CTLA-4) and programmed death 1 (PD-1), and agonistic antibodies targeting the costimulatory pathways OX40 and 4-1BB. Recent progress and opportunities for future investigation of combination antibody therapy will be described., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Primary T cell activation involves the integration of three distinct signals delivered in sequence: (1) antigen recognition, (2) costimulation, and (3) cytokine-mediated differentiation and expansion. Strong immunostimulatory events such as immunotherapy or infection induce profound cytokine release causing "bystander" T cell activation, thereby increasing the potential for autoreactivity and need for control. We show that during strong stimulation, a profound suppression of primary CD4(+) T-cell-mediated immune responses ensued and was observed across preclinical models and patients undergoing high-dose interleukin-2 (IL-2) therapy. This suppression targeted naive CD4(+) but not CD8(+) T cells and was mediated through transient suppressor of cytokine signaling-3 (SOCS3) inhibition of the STAT5b transcription factor signaling pathway. These events resulted in complete paralysis of primary CD4(+) T cell activation, affecting memory generation and induction of autoimmunity as well as impaired viral clearance. These data highlight the critical regulation of naive CD4(+) T cells during inflammatory conditions., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Since multiple lines of experimental and clinical data clearly identified regulatory T cells as an integral part of the immune response, these cells have become a major focus of investigation in tumor immunology. Regulatory T cells are in place to dampen ongoing immune responses and to prevent autoimmunity, but they also have profound effects in blocking therapeutic anti-tumor activity. Therefore regulatory T cells are seen as a major hurdle that must be overcome in order for cancer immunotherapy to reach its therapeutic potential. Regulatory T cells are heterogeneous with sub-populations that exhibit distinct functional features. Here we will review the individual sub-populations in regards to their mode of action and their potential impact on blocking anti-tumor immunity. Approaches to measure function and frequency of regulatory T cells in model systems and clinical trails will be discussed. Finally, we will describe possible ways to interfere with regulatory T cell-mediated immune suppression with the focus on recent pre-clinical and clinical findings.

The article focuses on the Advances in the Treatment of Melanoma . Topics discussed include highlights recent advances in the treatment of melanoma, including changes in staging, surgical management, and advances in systemic therapy for high-risk and advanced meloma; and the inclusion of sentinelnode status in the AJCC-8 melanoma staging system greatly improved prognostic information because of the ability to discriminate between node-negative and node-positive disease.

Background: Adoptive T cell therapy (ACT) has shown great promise in melanoma, with over 50% response rate in patients where autologous tumor-reactive tumor-infiltrating lymphocytes (TIL) can be cultured and expanded. A major limitation of ACT is the inability to generate or expand autologous tumor-reactive TIL in 25-45% of patients tested. Methods that successfully identify tumors that are not suitable for TIL generation by standard methods would eliminate the costs of fruitless expansion and enable these patients to receive alternate therapy immediately. Methods: Multispectral fluorescent immunohistochemistry with a panel including CD3, CD8, FoxP3, CD163, PD-L1 was used to analyze the tumor microenvironment in 17 patients with melanoma among our 36-patient cohort to predict successful TIL generation. Additionally, we compared tumor fragments and enzymatic digestion of tumor samples for efficiency in generating tumor-reactive TIL. Results: Tumor-reactive TIL were generated from 21/36 (58%) of melanomas and for 12/13 (92%) tumors where both enzymatic and fragment methods were compared. TIL generation was successful in 10/13 enzymatic preparations and in 10/13 fragment cultures; combination of both methods resulted in successful generation of autologous tumor-reactive TIL in 12/13 patients. In 17 patients for whom tissue blocks were available, IHC analysis identified that while the presence of CD8+ T cells alone was insufficient to predict successful TIL generation, the CD8+ to FoxP3+ ratio was predictive with a positive-predictive value (PPV) of 91% and negative-predictive value (NPV) of 86%. Incorporation of CD163+ macrophage numbers and CD8:PD-L1 ratio did not improve the PPV. However, the NPV could be improved to 100% by including the ratio of CD8+:PD-L1+ expressing cells. Conclusion: This is the first study to apply 7-color multispectral immunohistochemistry to analyze the immune environment of tumors from patients with melanoma. Assessment of the data using unsupervised hierarchical clustering identified tumors from which we were unable to generate TIL. If substantiated, this immune profile could be applied to select patients for TIL generation. Additionally, this biomarker profile may also indicate a pre-existing immune response, and serve as a predictive biomarker of patients who will respond to checkpoint blockade. We postulate that expanding the spectrum of inhibitory cells and molecules assessed using this technique could guide combination immunotherapy treatments and improve response rates. [ABSTRACT FROM AUTHOR]

Surface expression of the IL-2 receptor α-chain (CD25) has been used to discriminate between CD4+CD25HIFOXP3+ regulatory T (Treg) cells and CD4+CD25NEGFOXP3− non-Treg cells. However, this study reports that the majority of resting human memory CD4+FOXP3− T cells expresses intermediate levels of CD25 and that CD25 expression can be used to delineate a functionally distinct memory subpopulation. The CD25NEG memory T-cell population contains the vast majority of late differentiated cells that respond to antigens associated with chronic immune responses and are increased in patients with systemic lupus erythematosus (SLE). In contrast, the CD25INT memory T cells respond to antigens associated with recall responses, produce a greater array of cytokines, and are less dependent on costimulation for effector responses due to their expression of CD25. Lastly, compared to the CD25NEG and Treg-cell populations, the CD25INT memory population is lost to a greater degree from the blood of cancer patients treated with IL-2. Collectively, these results show that in humans, a large proportion of CD4+ memory T cells express intermediate levels of CD25, and this CD25INTFOXP3− subset is a functionally distinct memory population that is uniquely affected by IL-2. [ABSTRACT FROM AUTHOR]

OX40 is a member of the tumor necrosis factor (TNF) receptor family and a potent co-stimulatory pathway that when triggered can enhance T-cell memory, proliferation and anti-tumor activity in patients with metastatic cancer. Ongoing investigations at our institution have demonstrated that OX40 expressing T cells are found in abundance in the tumors of patients with advanced stage head and neck squamous cell carcinoma (HNSCC). This has led to the initiation of human clinical trials investigating OX40-directed therapy for patients with HNSCC in both the metastatic and curative setting. The purpose of this review is to explore what is known about OX40 signaling and discuss how this pathway potentially can be modulated to improve outcome for patients with HNSCC. [ABSTRACT FROM AUTHOR]

Abstract: OX40 (CD134) is a potent costimulatory molecule found on the surface of activated CD4+ and CD8+ T cells. Immunotherapy with OX40 agonists administered in vivo has demonstrated efficacy in several murine tumor models. A phase I clinical trial is currently underway in patients with advanced cancer using a mouse anti-CD134 monoclonal antibody. Therapy with this antibody will likely be limited to one cycle because patients develop neutralizing human anti-mouse antibody (HAMA). Therefore, we developed a humanized OX40 agonist that links the extracellular domain of human OX40L to the Fc domain of human IgG1 via a trimerizing isoleucine zipper domain (ILZ). Physical characterization by velocity sedimentation revealed that this novel construct, hFcILZOX40L, was assembled into hexamers in which the Fc domains formed three disulfide-bonded dimers and the ILZ-OX40L domains formed two trimers. Trimerization of the ILZ domain was necessary to achieve appropriate assembly. In vitro biologic activity of the hFcILZOX40L hexamer was equivalent to the activity of agonist antibodies in plate-bound assays and was superior when the agonists were tested as soluble agents. Our ultimate goal is to use this recombinant molecule in a future clinical trial, and we feel that the OX40L hexamer will have equivalent or superior agonist activity in vivo when compared to an anti-OX40 antibody. [Copyright &y& Elsevier]