Immunotherapy perspectives in the new era of B-cell editing

Abstract

Since the early days of vaccination, targeted immunotherapy has gone through multiple conceptual changes and challenges. It now provides the most efficient and up-to-date strategies for either preventing or treating infections and cancer. Its most recent and successful weapons are autologous T cells carrying chimeric antigen receptors, engineered purposely for binding cancer-specific antigens and therefore used for so-called adoptive immunotherapy. We now face the merger of such achievements in cell therapy: using lymphocytes redirected on purpose to bind specific antigens and the clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) revolution, which conferred genome-editing methodologies with both safety and efficacy. This unique affiliation will soon and considerably expand the scope of diseases susceptible to adoptive immunotherapy and of immune cells available for being reshaped as therapeutic tools, including B cells. Following the monumental success story of passive immunotherapy with monoclonal antibodies (mAbs), we are thus entering into a new era, where a combination of gene therapy/cell therapy will enable reprogramming of the patient’s immune system and notably endow his B cells with the ability to produce therapeutic mAbs on their own.

Recent advances in biomaterial-boosted adoptive cell therapy

“…Immune cell engineering has been regarded as a promising approach to substantially enhance the efficacy of transfused immune cells and immensely expand their therapeutic potential. 39,83–86 Chimeric antigen receptor (CAR)-T cell therapy, generated by virus-mediated genetic engineering, is one of the most studied clinically available adoptive cell therapy examples. 87 The CAR-NK cells reprogrammed using a similar virus-based engineering platform are also under clinical investigations.…”

In vivotracking ofex vivogenerated89Zr-oxine labeled plasma cells by PET in a non-human primate model

“…B cells are highly abundant and easily collected from peripheral blood without mobilization. 18,19 Primary human B cells can be many-fold expanded in vitro and differentiated to antibody secreting plasmablasts and mature, isotype-switched plasma cells. Challenges to B cell medicine approaches include inefficient transduction, achieving protein production at a level likely to be therapeutic, and manufacturing at scale.…”

Production of therapeutic levels of human FIX-R338L by engineered B cells using GMP-compatible medium

“… 2 Recent developments with precise editing technologies open the possibility of engineering plasmablast and plasma cells to act as autologous cell factories, capable of delivering sustained and high doses of therapeutic proteins. 3 , 4 , 5 In this study, ex vivo B cell engineering was performed by combining electroporation of zinc-finger nuclease (ZFN) mRNA with adeno-associated virus 6 (AAV6) donor DNA template delivery. 6 , 7 In the literature, to date, most B cell engineering methods use fetal bovine serum (FBS) or human AB serum in combination with classical research media such as DMEM, RPMI, or Iscove's modified Dulbecco's medium.…”