Development of a Safety Surveillance Plan for the Academic Medicine Sponsor Performing First-in-Human Cellular Therapy Clinical Trials: A Report from the Consortium for Pediatric Cellular Immunotherapy.

Pharmacovigilance (PV), also known as drug safety, is the science of risk management involving the detection, assessment, understanding, and prevention of adverse effects related to a medication. This discipline has traditionally focused on the postmarketing period, with less attention to early-phase clinical trials. However, during the immunotherapy and cellular therapy investigational stage, regulatory agencies are increasingly emphasizing the need to identify and characterize safety signals earlier in clinical development as part of a comprehensive safety surveillance plan. Compliance with PV and safety regulations are further heightened as cell and gene therapy (CGT) trials grow in complexity and scope owing to ever-changing and increasingly rigorous regulatory mandates. Based on this changing landscape, a critical aspect of early-phase trials of cellular products where significant safety events are anticipated is to ensure that every effort is made to protect clinical trial participants by maximizing attention to the risk-versus-benefit profile. This includes the development of robust plans for safety surveillance that provide a continual assessment of safety signals to enable safety reporting to regulatory bodies and the Food and Drug Administration, a regular analysis of aggregate safety data, and a plan to communicate safety findings. This report focuses on PV in early-phase clinical trials of first-in-human investigational products sponsored by academic centers in which the availability of PV resources and subject matter experts is limited. To more fully understand the challenges of CGT PV oversight within pediatric academic medical centers conducting early-phase clinical trials, a working group from institutions participating in the Consortium for Pediatric Cellular Immunotherapy composed of faculty and regulatory professionals was convened to compare experiences, identify best practices, and review published literature to identify commonalities and opportunities for alignment. Here we present guidelines on PV planning in early-phase CGT clinical trials occurring in academic medical centers and offer strategies to mitigate risk to trial participants. Standards to address regulatory requirements and governance for safety signal identification and risk assessment are discussed.

Evolving use of real-world evidence in the regulatory process: a focus on immuno-oncology treatment and outcomes.

In recent years, regulatory bodies have increasingly recognized the utility of real-world evidence (RWE) for supplementing and supporting clinical trial data in new drug applications. Nevertheless, the integration of RWE into established regulatory processes is complex and the generation of 'regulatory-grade' real-world data faces operational, methodological, data-related and policy-related challenges. In parallel with this evolving role for RWE, immuno-oncology therapies have emerged as leading cancer treatments and are expected to continue to play a central role in the future. In this article, we review the current literature on the use of RWE for regulatory submissions, with a focus on novel anticancer immunotherapies, and discuss the utility and current limitations of RWE in the context of drug development and regulatory approvals.

Drafting eligible biotech and immunotherapy claims.

The very recent US Supreme Court and Court of Appeals for Federal Circuit (CAFC) cases have dramatically changed the standard of patent eligibility. Several groundbreaking innovations were thus determined to be patent ineligible. The patent ineligibility would impact on the innovation s of the field of biomarkers, diagnostic methods and personalize cancer immunotherapy. To solve the thorny problem of eligibility, this study retrospectively analyzes all CAFC related cases and presents a flow chart determining patent eligibility based on the courts' decisions. Our analysis indicates the best way to avoid eligible rejection or invalidation is that an invention cannot fall within the categories of natural law, natural phenomenon or abstract idea. Thus, claiming non-natural cDNA, involving a step to grow a transformed cell or adding a means clause in a method claim would be some possible solutions. Moreover, based on the flow chart, even though a claim with substantive limitation but not well-understood, routine or conventional activities would be patent eligible; no one has successfully made the argument in the CAFC so far. We believe that this flow chart can serve as a set of guidelines for determining patent eligibility.

HMGB1 blockade significantly improves luminal fibrous obliteration in a murine model of bronchiolitis obliterans syndrome.

BACKGROUND: Although high-mobility group box-1 (HMGB1), which is a nuclear protein, was reported to enhance the allogeneic responses in transplantation, the effect of HMGB1 on bronchiolitis obliterans syndrome (BOS) is unknown. METHODS: A murine heterotopic tracheal transplantation model was used. Protein concentrations of HMGB1, interferon-γ (IFN-γ), interleukin (IL)-10, and IL-17 were analyzed in the isografts, allografts, controls, and HMGB1-neutralizing antibody administered allografts (n = 6; Days 1, 3, 5, 7, 14, 21, and 28). The luminal fibrous occlusion was analyzed (n = 6; Days 7, 14, 21, and 28). Infiltrating CD8 and CD4 T lymphocytes around the allografts and serum levels of IFN-γ and IL-10 were evaluated (n = 6; Day 7). RESULTS: The HMGB1 levels in the allografts were significantly increased compared with the isografts at Day 7. HMGB1 blockade did not change the IL-17 level, but decreased the IFN-γ/IL-10 ratio in the early phase (Days 5 and 7) and significantly improved the fibrous occlusion in the late phase (Days 14, 21, and 28). HMGB1 blockade significantly suppressed the CD8 T lymphocytes infiltration and decreased the serum IFN-γ/IL-10 ratio compared with the control at Day 7. CONCLUSIONS: HMGB1 may be a trigger of the BOS pathogenesis and candidate target for the treatment of the disease.

Clinical Development and Initial Approval of Novel Immune Checkpoint Inhibitors in Oncology: Insights From a Global Regulatory Perspective.

Immune checkpoint inhibitors (ICI) have demonstrated meaningful patterns of clinical efficacy across various cancers. During their development, novel regulatory strategies and clinical design approaches were explored. This metrics-based narrative review examines submission strategies and clinical evidence expectations of the US, European, and Japanese drug agencies, as well as their impact on approval and overall development times. Also discussed is the role of emerging clinical science and biomarker evaluation to get the first six ICI initially approved.

Reasons for Declining Venom Immunotherapy.

INTRODUCTION: Hymenoptera venom allergy is associated with significant morbidity and deterioration in health-related quality of life, and risk of fatal systemic reactions. Although venom immunotherapy is safe and the only effective treatment in allergic individuals, some patients prefer not to pursue this treatment. Since 2011, when the 50% reimbursement was stopped, patients must fully support the cost of immunotherapy. This study aimed to ascertain the reasons why patients decline immunotherapy. MATERIAL AND METHODS: A medical records review of all patients proposed to receive venom immunotherapy at an Allergy and Clinical Immunology Department in Porto, Portugal, between 2006 and 2015, followed by a phone interview to patients refusing treatment. RESULTS: A total of 83 subjects were enrolled, with a mean (± SD) age of 44.4 (14.7) years and 55 (66%) males; 27 refused venom immunotherapy between 2006 and 2015. Nineteen were interviewed and 14 of those stated price as the main reason for declining treatment. The only identified risk factor associated with immunotherapy refusal was being proposed after 2011 (OR: 3.29; 95% CI: 1.12 - 9.68; p = 0.03). DISCUSSION: The number of patients refusing venom immunotherapy doubled since reimbursement was withdrawn. Price was identified as the major obstacle to treatment completion. Immunotherapy proposal after reimbursement was stopped was associated with a 3-fold increase in the risk of refusing treatment. CONCLUSION: These findings show how economic decisions may have a detrimental effect on patient care, as immunotherapy refusal left them exposed to an avoidable life-threatening risk.

Introdução: A alergia a veneno de himenópteros está associada a uma significativa morbilidade e diminuição da qualidade de vida, bem como a risco de reações alérgicas fatais. Apesar da imunoterapia com veneno de himenópteros ser um tratamento seguro e o único eficaz nesta patologia, alguns doentes decidem não o realizar. Desde 2011, quando a comparticipação de 50% terminou, o custo da imunoterapia é totalmente suportado pelos doentes. Este trabalho pretendeu identificar os motivos da recusa desta terapêutica. Material e Métodos: Revisão dos registos clínicos de todos os doentes propostos para imunoterapia com veneno de himenópteros num serviço de Imunoalergologia, no período 2006 - 2015, seguida de entrevista telefónica aos que a recusaram. Resultados: Foram incluídos 83 doentes, com uma idade média (± DP) de 44,4 (14,7) anos. Cinquenta e cinco (66%) eram homens; 27 recusaram imunoterapia entre 2006 e 2015. Dezanove foram entrevistados e 14 identificaram o preço como principal motivo de recusa. O único fator de risco identificado para a recusa de imunoterapia foi ser proposta depois de 2011 (OR: 3,29; 95% CI: 1,12 ­ 9,68; p = 0,03). Discussão: O número de doentes a recusar imunoterapia duplicou desde que a comparticipação foi retirada. O preço foi o principal obstáculo à realização do tratamento. Ser proposto após o término da comparticipação do tratamento aumentou em três vezes o risco de recusa. Conclusão: Estes achados revelam o impacto negativo de uma decisão económica na saúde e segurança destes doentes, já que a recusa da imunoterapia os manteve expostos a um risco de vida evitável.

Regulatory perspective on in vitro potency assays for human dendritic cells used in anti-tumor immunotherapy.

Dendritic cells (DCs) are key connectors between the innate and adaptive immune system and have an important role in modulating other immune cells. Therefore, their therapeutic application to steer immune responses is considered in various disorders, including cancer. Due to differences in the cell source and manufacturing process, each DC medicinal product is unique. Consequently, release tests to ensure consistent quality need to be product-specific. Although general guidance concerning quality control testing of cell-based therapies is available, cell type-specific regulation is still limited. Especially guidance related to potency testing is needed, because developing an in vitro assay measuring cell properties relevant for in vivo functionality is challenging. In this review, we provide DC-specific guidance for development of in vitro potency assays for characterisation and release. We present a broad overview of in vitro potency assays suggested for DC products to determine their anti-tumor functionality. Several advantages and limitations of these assays are discussed. Also, we provide some points to consider for selection and design of a potency test. The ideal functionality assay for anti-tumor products evaluates the capacity of DCs to stimulate antigen-specific T cells. Because this approach may not be feasible for release, use of surrogate potency markers could be considered, provided that these markers are sufficiently linked to the in vivo DC biological activity and clinical response. Further elucidation of the involvement of specific DC subsets in anti-tumor responses will result in improved manufacturing processes for DC-based products and should be considered during potency assay development.

Toward precision manufacturing of immunogene T-cell therapies.

Cancer can be effectively targeted using a patient's own T cells equipped with synthetic receptors, including chimeric antigen receptors (CARs) that redirect and reprogram these lymphocytes to mediate tumor rejection. Over the past two decades, several strategies to manufacture genetically engineered T cells have been proposed, with the goal of generating optimally functional cellular products for adoptive transfer. Based on this work, protocols for manufacturing clinical-grade CAR T cells have been established, but these complex methods have been used to treat only a few hundred individuals. As CAR T-cell therapy progresses into later-phase clinical trials and becomes an option for more patients, a major consideration for academic institutions and industry is developing robust manufacturing processes that will permit scaling-out production of immunogene T-cell therapies in a reproducible and efficient manner. In this review, we will discuss the steps involved in cell processing, the major obstacles surrounding T-cell manufacturing platforms and the approaches for improving cellular product potency. Finally, we will address the challenges of expanding CAR T-cell therapy to a global patient population.

Nucleic Acid Sensing Machinery: Targeting Innate Immune System for Cancer Therapy.

BACKGROUND: Nucleic acid sensing is an essential strategy employed by the innate immune system to detect both pathogen-derived nucleic acids and self-DNA released by host apoptotic or necrotic cells. The presence of nucleic acids that gain access to the cytoplasm is perceived by mammalian cells as "stranger" or "danger" signals that trigger a myriad of immunological responses. Recent publications have highlighted the importance of nucleic acid sensing machinery as mediator of innate and adaptive immunity, and cGAS, STING and RIG-I agonists have been validated as immunooncology agents in cancer therapy. OBJECTIVE: The crucial role of cGAS and STING in eliciting innate and adaptive immune responses provides a scientific rationale for using cGAMP and STING agonists both in human preventive vaccine and immunotherapy settings. Thus, search for natural and synthetic STING agonists and development of cyclic dinucleotides (CDNs)-based adjuvants were strongly intensified. Furthermore, with their ability to induce tumour cell death and lymphocyte cross priming, RIG-I ligands are among the most promising molecules for the development of new immunostimulatory adjuvants in cancer vaccines. RESULTS: This work focuses on relevant recent patents (2010-2017) that entail the use of nucleic acid sensing machinery to elicit innate and adaptive immune responses, highlighting a new approach in immune-mediated cancer therapy. Several patents describe compositions and methods that may be used as immuno-oncology agents for the treatment of cancer patients. cGAS and/or STING pathways modulating compounds alone or in combination with pharmaceutical compositions are discussed. New approaches to improve DNA-vaccine induced adaptive immunity for cancer therapy through increasing the level of plasmid-mediated activation of innate immune signalling pathways are also discussed. In addition, a targeted selection of very recent clinical studies describing the employment of innate immunity targeting compounds is reported. CONCLUSION: It is highly relevant to deepen the study of the nucleic acid-sensing mechanisms to develop new pharmacological approaches to engage these pathways within the tumour microenvironment. Indeed, further clarification will be functional to develop advanced anticancer strategies or to design new vaccine formulations.

The FDA Oncology Center of Excellence and precision medicine.

In January 2017, the U.S. Food and Drug Administration (FDA) formally established the Oncology Center of Excellence (OCE) to streamline the development of cancer therapies by uniting experts from FDA product centers to conduct expedited review of drugs, biologics, and devices. In May 2017, the FDA approved a cancer treatment based on a biomarker, without regard to the tumor's site, by granting accelerated approval to pembrolizumab for patients with solid tumors that have the microsatellite instability-high or mismatch repair deficient biomarker. We describe here the OCE's role in this first site-agnostic approval and OCE programs for further advancement of oncology-related regulatory science and policy. In addition, the FDA's four expedited review programs that enable transformative therapies to reach patients with life-threatening malignancies earlier in the development process are key to the continued rapid development of safe and effective therapies for patients with few or no other treatment options. These changes at FDA are taking place in the context of recent progress in the understanding of the genetic and immunologic foundations of cancer, resulting in the development of targeted therapies and immunotherapies. The traditional system of phased clinical trials has evolved as early trials of breakthrough therapies use expansion cohorts in a process known as seamless drug development. Increasingly, FDA approvals of targeted therapies are likely to have contemporaneous approvals of companion diagnostics to identify patients whose cancers harbor actionable abnormalities. Impact statement This publication describes the U.S. Food and Drug Administration's (FDA) first site-agnostic oncology drug approval, a landmark event in the history of cancer drug development. The role of the FDA's newly established Oncology Center of Excellence (OCE) in this approval is described, as are several OCE programs to advance excellence in regulatory science in the era of precision medicine. Also provided is an overview of FDA's expedited drug review programs, which are important to the continued acceleration of therapeutics development for patients with life-threatening diseases and few or no other treatment options.

Advances in personalized cancer immunotherapy.

There are currently three major approaches to T cell-based cancer immunotherapy, namely, active vaccination, adoptive cell transfer therapy and immune checkpoint blockade. Recently, this latter approach has demonstrated remarkable clinical benefits, putting cancer immunotherapy under the spotlight. Better understanding of the dynamics of anti-tumor immune responses (the "Cancer-Immunity Cycle") is crucial for the further development of this form of treatment. Tumors employ multiple strategies to escape from anti-tumor immunity, some of which result from the selection of cancer cells with immunosuppressive activity by the process of cancer immunoediting. Apart from this selective process, anti-tumor immune responses can also be inhibited in multiple different ways which vary from patient to patient. This implies that cancer immunotherapy must be personalized to (1) identify the rate-limiting steps in any given patient, (2) identify and combine strategies to overcome these hurdles, and (3) proceed with the next round of the "Cancer-Immunity Cycle". Cancer cells have genetic alterations which can provide the immune system with targets by which to recognize and eradicate the tumor. Mutated proteins expressed exclusively in cancer cells and recognizable by the immune system are known as neoantigens. The development of next-generation sequencing technology has made it possible to determine the genetic landscape of human cancer and facilitated the utilization of genomic information to identify such candidate neoantigens in individual cancers. Future immunotherapies will need to be personalized in terms of the identification of both patient-specific immunosuppressive mechanisms and target neoantigens.

ATMPs for Cancer Immunotherapy: A Regulatory Overview.

This chapter discusses European regulatory requirements for development of advanced therapy medicinal products (ATMP) for cancer immunotherapy approaches, describing the framework for clinical trials and for marketing authorization.Regulatory critical issues and challenges for developing ATMP are also discussed, with focus on potency determination, long-term follow-up, comparability, and insertional mutagenesis issues. Some of the most critical features of GMP application to ATMP are also described.

Extending the market exclusivity of therapeutic antibodies through dosage patents.

Dosage patents are one way to extend the market exclusivity of an approved drug beyond the lifetime of the patent that protects the drug as such. Dosage patents may help to compensate the applicant for the long period where the active pharmaceutical ingredient as such is already under patent prosecution, but not on the market yet, due to lengthy development and approval procedures. This situation erodes part of the time the drug is marketed under patent protection. Dosage patents filed at a later date can provide remedy for this problem. Examples of successful and unsuccesful attempts, and the reasons for the respective outcomes, are provided in this article.

Rituximab: Recommendations of the French Vasculitis Study Group (FVSG) for induction and maintenance treatments of adult, antineutrophil cytoplasm antibody-associated necrotizing vasculitides.

Increasing rituximab prescription for ANCA-associated necrotizing vasculitides justifies the publication of recommendations for clinicians. Rituximab is approved in the United States to induce and maintain remission. In Europe, rituximab was recently approved for remission induction. However, governmental agencies' approvals cannot replace clinical practice guidelines. Herein, the French Vasculitis Study Group Recommendations Committee, comprised of physicians with extensive experience in the treatment of vasculitides, presents its consensus guidelines based on literature analysis, the results of prospective therapeutic trials and personal experience.