Basics of advanced therapy medicinal product development in academic pharma and the role of a GMP simulation unit.

Following successes of authorized chimeric antigen receptor T-cell products being commercially marketed in the United States and European Union, product development of T-cell-based cancer immunotherapy consisting of cell-based advanced therapy medicinal products (ATMPs) has gained further momentum. Due to their complex characteristics, pharmacological properties of living cell products are, in contrast to classical biological drugs such as small molecules, more difficult to define. Despite the availability of many new advanced technologies that facilitate ATMP manufacturing, translation from research-grade to clinical-grade manufacturing in accordance with Good Manufacturing Practices (cGMP) needs a thorough product development process in order to maintain the same product characteristics and activity of the therapeutic product after full-scale clinical GMP production as originally developed within a research setting. The same holds true for transferring a fully developed GMP-grade production process between different GMP facilities. Such product development from the research to GMP-grade manufacturing and technology transfer processes of established GMP-compliant procedures between facilities are challenging. In this review, we highlight some of the main obstacles related to the product development, manufacturing process, and product analysis, as well as how these hinder rapid access to ATMPs. We elaborate on the role of academia, also referred to as 'academic pharma', and the added value of GMP production and GMP simulation facilities to keep innovation moving by reducing the development time and to keep final production costs reasonable.

Identification of a tumor-specific allo-HLA-restricted γδTCR.

γδT cells are key players in cancer immune surveillance because of their ability to recognize malignant transformed cells, which makes them promising therapeutic tools in the treatment of cancer. However, the biological mechanisms of how γδT-cell receptors (TCRs) interact with their ligands are poorly understood. Within this context, we describe the novel allo-HLA-restricted and CD8α-dependent Vγ5Vδ1TCR. In contrast to the previous assumption of the general allo-HLA reactivity of a minor fraction of γδTCRs, we show that classic anti-HLA-directed, γδTCR-mediated reactivity can selectively act on hematological and solid tumor cells, while not harming healthy tissues in vitro and in vivo. We identified the molecular interface with proximity to the peptide-binding groove of HLA-A*24:02 as the essential determinant for recognition and describe the critical role of CD8 as a coreceptor. We conclude that alloreactive γδT-cell repertoires provide therapeutic opportunities, either within the context of haplotransplantation or as individual γδTCRs for genetic engineering of tumor-reactive T cells.

Hunting for clinical translation with innate-like immune cells and their receptors.

Allogeneic stem cell transplantation (allo-SCT) has so far been the most effective immunotherapy for hematological malignancies. However, it is becoming increasingly clear that the immunotherapeutic concepts underlying allo-SCT as well as the traditional dissection of the immune system into innate and adaptive arms need substantial refinement. More and more cell types migrate into the interface between innate and adaptive immunity, creating new terms such as innate-like lymphocytes. These innate-like cells, which include natural killer (NK) cells and γδT cells, could provide unique advantages to therapeutic interventions aimed at treating hematological malignancies, including protection against tumor relapse and viral infections without causing harmful graft-versus-host disease (GVHD). Recent molecular and conceptual insights into these subpopulations have opened new avenues to exploit their exciting features for the development of new compounds and to revisit current therapeutic standards in the treatment of hematological cancers. This review therefore aims to discuss the rapid progress in the understanding of molecular mechanisms by which NK cells and γδT cells recognize malignancies and viral infections, and the value of this increasing knowledge to complement the battle against life-threatening complications of current strategies to treat cancer.