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CAR T cell therapies in multiple myeloma
system consisting of CRISPR guide-RNA and dead Cas9 fused to Clo51 nuclease, and (iii) a nano-particle delivery system carrying the gene for an anti-BCMA Centyrin- based CAR with a fully human binding domain. Rimiducid, a lipid-permeable tacrolimus analogue and protein dimerizer, may be administered for safety switch activation.96 Two phase I dose escalation and cohort expansion studies have recently been initiated. The CTX120 (clinicaltrials gov. Identifier: NCT04244656) is using anti-BCMA allogeneic CRISPR-Cas9-engineered T cells and the PBCAR269A (clinicaltrials gov. Identifier: NCT04171843) which applies its own gene editing tool (ARCUS) for GvHD risk reduction.
Integration of chimeric antigen receptor T cells into clinical routine - FACT-JACIE* standards and EBMT** guidelines
Since 2018, with version 7.0, the *Joint Accreditation Committee of ISCT and the **European Bone Marrow Transplantation Group (EBMT) (JACIE) prerequisites for cell therapy accreditation have included standards for infusions of immune-effector cells and CAR-T. The cur- rent recommendation is that CAR-T should be adminis- tered within the framework of an accredited allogeneic transplant program. The Foundation for the Accreditation of Cellular Therapy (FACT)-JACIE do not cover the man- ufacturing of CAR-T but do include supply chain and han- dover of responsibilities when the product is provided by third party. Overall, JACIE standards are structured on the basis of three major functional areas in cellular therapy: cell collection, laboratory processing, and clinical program. All areas required dedicated and highly qualified person- nel. Accredited programs for cell therapy must implement a product labeling system that guarantees identification and traceability from collection to manufacturing site and return to clinical units. EBMT recommendations further stress the importance of staff training97 and of multidisci- plinary approaches with teams who include transplant physicians along with qualified internal medicine sub-spe- cialists after a specific education program. Importantly, CAR-T infusions should be coordinated with intensive care specialists. All accredited centers must implement a policy for rapid escalation of care for critically ill patients including availability of specific drugs (i.e., tocilizumab). Though complications may vary among CAR-T products, they tend to follow a predictable timeline contributing to bed-planning decisions. Recent reports allow designing protocols for anti-infective prophylaxis and common post- infusion complications such as infections and tumor lysis syndrome.98 Inevitably, the unfortunate COVID-19 pan- demic stresses the importance of scrupulous adherence to
recommended hygiene procedures.99 Importantly, an EBMT registry, for all transplant centers accredited for cell therapies, has been created to collect date on efficacy, side effects and clinical outcomes for post-marketing surveil- lance.
Conclusions
The clinical role of CAR-T in the current armamentari- um of MM treatments remains as yet to be fully deter- mined. Moreover, other promising forms of antibody- based immunotherapies have been added. Despite some limitations of CAR-T therapy experienced in early studies in MM, one advantage of this cellular therapy is the inher- ent potential to finetune its design. Simpler structures and multi-target approaches may significantly improve effica- cy and safety. Constant learning to handle CAR-T therapy may also enable better patient-centered management. Last, long-term outcome studies and specific detection and analysis of CAR-T dynamics in vivo are essential to allow deeper understanding of their inherent functions which will facilitate future designs of improved CAR-T products. However, selecting patients who may most ben- efit from CAR-T and best timing of their administration still require rather lengthy and thorough clinical investiga- tions. One more challenge that lies ahead will be the cost effectiveness of future commercial products. This issue has already been addressed in patients with lymphoma where cost reductions will be inevitable to make CAR-T sustainable therapies for health care systems.100 Despite all remaining open questions and issues that still need to be addressed, and hopefully answered and resolved within the next years, we are now, without any doubt, at the dawn of a new era that will significantly improve patient outcome.
Disclosures
No conflicts of interest to disclose.
Contributions
BB, ME, NWCJD designed the review and wrote the manu- script; LG, MD, FG, ET, LGRL, SD, NG, NK, RP and ET provided data and interpretation; MAD, PS, HE and MB reviewed the manuscript.
Funding
LGRL as BITRECS fellow has received funding from the European Union’s Horizon 2020 research and innovation pro- gramme under the Marie Sklodowska-Curie grant agreement No 754550 and from “La Caixa” Foundation. SD has received funding from the Mildred Scheel Early Career Center funded by the German Cancer Aid.
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