Best Practices and Considerations for Clinical Pharmacology and Pharmacometric Aspects for Optimal Development of CAR‐T and TCR‐T Cell Therapies: An Industry Perspective

Abstract

With the promise of a potentially “single dose curative” paradigm, CAR‐T cell therapies have brought a paradigm shift in the treatment and management of hematological malignancies. Both CAR‐T and TCR‐T cell therapies have also made great progress toward the successful treatment of solid tumor indications. The field is rapidly evolving with recent advancements including the clinical development of “off‐the‐shelf” allogeneic CAR‐T therapies that can overcome the long and difficult “vein‐to‐vein” wait time seen with autologous CAR‐T therapies. There are unique clinical pharmacology, pharmacometric, bioanalytical, and immunogenicity considerations and challenges in the development of these CAR‐T and TCR‐T cell therapies. Hence, to help accelerate the development of these life‐saving therapies for the patients with cancer, experts in this field came together under the umbrella of International Consortium for Innovation and Quality in Pharmaceutical Development (IQ) to form a joint working group between the Clinical Pharmacology Leadership Group (CPLG) and the Translational and ADME Sciences Leadership Group (TALG). In this white paper, we present the IQ consortium perspective on the best practices and considerations for clinical pharmacology and pharmacometric aspects toward the optimal development of CAR‐T and TCR‐T cell therapies.

Clinical Pharmacology Considerations for the “Off‐the‐Shelf” Allogeneic Cell Therapies

“…Typically after infusion, CAR-T levels are found to be higher in responders as compared with nonresponders. [5][6][7]26 For allogeneic CAR-T programs, similar exposure-efficacy trends are also observed from ongoing early clinical studies. Higher expansion (C max , AUC 0-28d , or AUC to the last measurable timepoint (AUC last )) was reported in responders as compared with nonresponders for UCART19 (anti-CD19 CAR-T for r/r B-cell ALL), 25 ALLO-715 (anti-BCMA CAR-T in patients with r/r MM), 32 ALLO-501 (anti-CD19 CAR-T for r/r large B cell lymphoma (LBCL) and follicular lymphoma), 43,44 and RD13-01 (anti-CD7 CAR-T for r/r T-cell ALL/lymphoblastic leukemia).…”

“…25 Dose-exposure (i.e., dose-CK) and dose-response relationship for allogeneic CAR-T therapies Dose-exposure-response relationships have been investigated for autologous cell therapies and summarized previously for different products. [5][6][7]26 For these products, no strong positive dose-exposure or dose-response (safety or efficacy) correlations are generally observed. Whereas exposure may generally increase with dose for some autologous therapies (for example, in case of BCMA-targeting ide-cel in patients with multiple myeloma (MM)), there is commonly significant overlap in exposures across dose levels.…”

“…There are a multitude of patient-and product-specific factors that have been shown to impact dose-exposure-response relationship for autologous CAR-T therapies. [5][6][7]26 Although some of these factors remain uncontrollable, others can be controlled, selected, and optimized during the development of allogeneic cell therapies (e.g., product-related factors, such as CD4:CD8 ratio and immune phenotype, as well as patient-related intrinsic and extrinsic factors, such as tumor burden and lymphodepleting regimen).…”

“…In addition to the "dose, " as represented by the infused number of cells, patient-and productrelated factors may be key drivers for cellular kinetics (CKs) and clinical outcomes. [5][6][7] On top of that, allogeneic cell therapies present their own unique clinical pharmacology challenges due to higher potential for rejection and generally shorter persistence as compared with autologous therapies (Table 1). In this review, we first highlight the current development landscape of allogeneic cell therapies including CAR-T, CAR-NK, and γδ-T cells, along with unique cell engineering considerations (Table 2).…”

Novel Therapeutic Modalities: The Future is Now

“…17 In another White Paper, Mody and collaborators from the International Consortium for Innovation and Quality in Pharmaceutical Development present an industry perspective on best clinical pharmacology practices for the development of CAR-T and T cell receptor T cell therapies, including clinical study design and modeling and simulation strategies, underscoring the unique and critical role of clinical pharmacology. 18 This is further exemplified in the study by Masilamani et al, 19 who compare bioanalytical methods for characterization of CAR-T cellular kinetics. Unlike proteins or antibodies, CAR-T are "living cell" therapies whose pharmacokinetics (PKs) are characterized by expansion, distribution, contraction, and persistence.…”