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Key Points CD123 CAR T cells specifically target CD123+ AML cells. AML patient-derived T cells can be genetically modified to lyse autologous tumor cells.

The success of adoptive therapy using chimeric antigen receptor (CAR)-expressing T cells partly depends on optimal CAR design. CARs frequently incorporate a spacer/linker region based on the constant region of either IgG1 or IgG4 to connect extracellular ligand-binding with intracellular signaling domains. Here, we evaluated the potential for the IgG4-Fc linker to result in off-target interactions with Fc gamma receptors (FcγRs). As proof-of-principle, we focused on a CD19-specific scFv-IgG4-CD28-zeta CAR and found that, in contrast to CAR-negative cells, CAR+ T cells bound soluble FcγRs in vitro and did not engraft in NSG mice. We hypothesized that mutations to avoid FcγR binding would improve CAR+ T cell engraftment and antitumor efficacy. Thus, we generated CD19-specific CARs with IgG4-Fc spacers that had either been mutated at two sites (L235E; N297Q) within the CH2 region (CD19R(EQ)) or incorporated a CH2 deletion (CD19Rch2Δ). These mutations reduced binding to soluble FcγRs without altering the ability of the CAR to mediate antigen-specific lysis. Importantly, CD19R(EQ) and CD19Rch2Δ T cells exhibited improved persistence and more potent CD19-specific antilymphoma efficacy in NSG mice. Together, these studies suggest that optimal CAR function may require the elimination of cellular FcγR interactions to improve T cell persistence and antitumor responses.

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SYCHOLOGISTS have only recently begun to show an interest in the relationships between the structure of groups and their problem-solving effectiveness. Rosenberg, Erlick, and Berkowitz (9) have demonstrated an "assembly effect" in the group product, an effect based not on the characteristics of each person but on the relations of the characteristics of each individual to those of the others in the group. Schutz (10) showed that the performances of "compatible" groups were superior to those of "incompatible" groups on two tasks. In these studies, as in most problemsolving experiments, the nature of the tasks used was undefined. Certain questions remain unanswered; Does an "assembly effect" occur on all tasks? Are "compatible" groups superior on every type of problem?The present experiment examined the interrelationships among different group structures and different task characteristics, as these interrelationships determined the "quality" and "acceptance" of the group product (6). The groups varied in the degree of similarity or homogeneity of their members' personalities. The effects of these variations were examined in terms of the quality and acceptance of solutions to two different problems. One problem involved quality alone; the other involved acceptance and quality. DEVELOPMENT OF HYPOTHESESBoth Maier (5) and Duncker (1) have emphasized the importance of the "direction" or initial orientation toward a problem in the problem-solving behaviors of individuals.1 This article has been adapted from a dissertation submitted in partial fulfillment of the requirements for the degree of doctor of philosophy at the University of Michigan (3). The author wishes to express appreciation to Norman R, F. Maier for his continuing interest and stimulating guidance in the research and in the preparation of this report. Thanks are also offered to Arnold Tannenbaum and Annette Wigod for constructive criticisms of this article.