Chimeric Antigen Receptor T Cells This review addresses T-cell engineering and synthetic immunity, with a focus on producing durable remissions in patients with treatment-refractory tumors. Toxic e...

https://www.nejm.org/doi/pdf/10.1056/NEJMra1706169

Chimeric Antigen Receptor Therapy.

Monoclonal antibodies (mAbs) are now established as targeted therapies for malignancies, transplant rejection, autoimmune and infectious diseases, as well as a range of new indications. However, administration of mAbs carries the risk of immune reactions such as acute anaphylaxis, serum sickness and the generation of antibodies. In addition, there are numerous adverse effects of mAbs that are related to their specific targets, including infections and cancer, autoimmune disease, and organ-specific adverse events such as cardiotoxicity. In March 2006, a life-threatening cytokine release syndrome occurred during a first-in-human study with TGN1412 (a CD28-specific superagonist mAb), resulting in a range of recommendations to improve the safety of initial human clinical studies with mAbs. Here, we review some of the adverse effects encountered with mAb therapies, and discuss advances in preclinical testing and antibody technology aimed at minimizing the risk of these events.

/pdf/the-safety-and-side-effects-of-monoclonal-antibodies-ebefjsrh6s.pdf

The safety and side effects of monoclonal antibodies

Microengineered cell culture systems are becoming sufficiently sophisticated that they can recapitulate many of the phenomena observed in tissues and organisms. Here, Huh and colleagues discuss the advances made in these 'organs-on-chips' and how they could be used in drug development, including target identification and validation, toxicity screening and stratified medicine.

/pdf/organs-on-chips-at-the-frontiers-of-drug-discovery-42uirytgwk.pdf

Organs-on-chips at the frontiers of drug discovery

https://doi.org/10.1016/j.apsb.2022.02.002

Why 90% of clinical drug development fails and how to improve it?

Cancer immunotherapies targeting adaptive immune checkpoints have substantially improved patient outcomes across multiple metastatic and treatment-refractory cancer types. However, emerging studies have demonstrated that innate immune checkpoints, which interfere with the detection and clearance of malignant cells through phagocytosis and suppress innate immune sensing, also have a key role in tumour-mediated immune escape and might, therefore, be potential targets for cancer immunotherapy. Indeed, preclinical studies and early clinical data have established the promise of targeting phagocytosis checkpoints, such as the CD47-signal-regulatory protein α (SIRPα) axis, either alone or in combination with other cancer therapies. In this Review, we highlight the current understanding of how cancer cells evade the immune system by disrupting phagocytic clearance and the effect of phagocytosis checkpoint blockade on induction of antitumour immune responses. Given the role of innate immune cells in priming adaptive immune responses, an improved understanding of the tumour-intrinsic processes that inhibit essential immune surveillance processes, such as phagocytosis and innate immune sensing, could pave the way for the development of highly effective combination immunotherapy strategies that modulate both innate and adaptive antitumour immune responses.

/pdf/phagocytosis-checkpoints-as-new-targets-for-cancer-4fwsdeqy2i.pdf

Phagocytosis checkpoints as new targets for cancer immunotherapy.

A key part of drug discovery and development is the characterization and optimization of the safety and efficacy of drug candidates to identify those that have an appropriately balanced safety-efficacy profile for a given indication The therapeutic index (TI)--which is typically considered as the ratio of the highest exposure to the drug that results in no toxicity to the exposure that produces the desired efficacy--is an important parameter in efforts to achieve this balance Various types of safety and efficacy data are generated in vitro and in vivo (in animals and in humans), and these data can be used to predict the clinical TI of a drug candidate at an early stage However, approaches to systematically and quantitatively compare these types of data and to apply this knowledge more effectively are needed This article critically discusses the various aspects of TI determination and interpretation in drug development for both small molecule drugs and biotherapeutics

The determination and interpretation of the therapeutic index in drug development

Most therapeutic monoclonal antibodies (mAbs) licensed for human use or in clinical development are indicated for treatment of patients with cancer and inflammatory/autoimmune disease and as such, are designed to directly interact with the immune system. A major hurdle for the development and early clinical investigation of many of these immunomodulatory mAbs is their inherent risk for adverse immune-mediated drug reactions in humans such as infusion reactions, cytokine storms, immunosuppression and autoimmunity. A thorough understanding of the immunopharmacology of a mAb in humans and animals is required to both anticipate the clinical risk of adverse immunotoxicological events and to select a safe starting dose for first-in-human (FIH) clinical studies. This review summarizes the most common adverse immunotoxicological events occurring in humans with immunomodulatory mAbs and outlines non-clinical strategies to define their immunopharmacology and assess their immunotoxic potential, as well as reduce the risk of immunotoxicity through rational mAb design. Tests to assess the relative risk of mAb candidates for cytokine release syndrome, innate immune system (dendritic cell) activation and immunogenicity in humans are also described. The importance of selecting a relevant and sensitive toxicity species for human safety assessment in which the immunopharmacology of the mAb is similar to that expected in humans is highlighted, as is the importance of understanding the limitations of the species selected for human safety assessment and supplementation of in vivo safety assessment with appropriate in vitro human assays. A tiered approach to assess effects on immune status, immune function and risk of infection and cancer, governed by the mechanism of action and structural features of the mAb, is described. Finally, the use of immunopharmacology and immunotoxicity data in determining a minimum anticipated biologic effect Level (MABEL) and in the selection of safe human starting dose is discussed.

https://www.tandfonline.com/doi/pdf/10.4161/mabs.2.3.11782

Safety and immunotoxicity assessment of immunomodulatory monoclonal antibodies.

The minimum anticipated biological effect level (MABEL) for selection of first human dose in clinical trials with monoclonal antibodies.

Limited sensitivity and limited target organ specificity are the major drawbacks for most peripheral clinical pathology parameters traditionally used for monitoring organ integrity both during preclinical toxicological assessment and clinical safety testing of investigational drugs. Several novel toxicity biomarkers have emerged as sensitive tools for detection, monitoring, quantification and prediction of solid organ toxicity. These tissue-specific, non-invasive biomarkers may provide valuable information for decision making during toxicological assessment and may be used for sensitive and specific target organ monitoring during clinical trials. This review critically discusses the opportunities and limitations of these biomarkers with respect to their translation into (first-in-human) clinical trials. A comprehensive overview is provided on serum- and urine-based biomarkers for hepatotoxicity, nephrotoxicity, cardiotoxicity, gonadotoxicity, pancreatic toxicity, vascular toxicity and phospholipidosis including species-specific assay availabilities and sampling regimens. In addition, the current regulatory status is presented and discussed in view of recent changes in regulatory acceptance by health authorities.

Tissue-specific, non-invasive toxicity biomarkers: translation from preclinical safety assessment to clinical safety monitoring.

Comparative requirements for exploratory clinical trials — eIND, eCTA and microdosing ☆

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