TCR-T( Joint Biosciences)

Eribulin inhibits microtubule polymerization and improves the overall survival of patients with recurrent metastatic breast cancer. A subgroup analysis revealed a low neutrophil to lymphocyte ratio (NLR) (<3) to be a prognostic factor of eribulin treatment. We thus hypothesized that eribulin might be related to the immune response for breast cancer cells and we analyzed the effects of eribulin on the immune system. Immunohistochemical staining revealed that human leukocyte antigen (HLA) class I expression was increased in clinical samples after eribulin treatment. In vitro assays revealed that eribulin treatment increased HLA class I expression in breast cancer line cells. RNA‐sequencing demonstrated that eribulin treatment increased the expression of the NOD‐like family CARD domain‐containing 5 (NLRC5), a master regulator of HLA class I expression. Eribulin treatment increased the NY‐ESO‐1‐specific T‐cell receptor (TCR) transduced T (TCR‐T) cell response for New York oesophageal squamous cell carcinoma 1 (NY‐ESO‐1) overexpressed breast cancer cells. The eribulin and TCR‐T combined therapy model revealed that eribulin and immunotherapy using TCR‐T cells has a synergistic effect. In summary, eribulin increases the expression of HLA class 1 via HLA class 1 transactivatior NLRC5 and eribulin combination with immunotherapy can be effective for the treatment of breast cancer.

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.