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Immunol."],"abstract":"<jats:p>A deeper understanding of basic immunology principles and advances in bioengineering\u00a0have accelerated the mass production of genetically-reprogrammed T-cells as living drugs to treat human diseases. Autologous and allogeneic cytotoxic T-cells have been weaponized to brandish MHC-independent chimeric antigen receptors (CAR) that specifically engage antigenic regions on tumor cells. Two distinct CAR-based therapeutics designed to target BCMA are now FDA-approved based upon robust, sustained responses in heavily-pretreated multiple myeloma (MM) patients enrolled on the KarMMa and CARTITUDE-1 studies. While promising, CAR T-cells present unique challenges such as antigen escape and T-cell exhaustion. Here, we review novel strategies to design CARs that overcome current limitations. Co-stimulatory signaling regions were added to second-generation CARs to promote IL-2 synthesis, activate T-cells and preclude apoptosis. Third-generation CARs are composed of multiple co-stimulatory signaling units, e.g., CD28, OX40, 4-1BB, to reduce exhaustion. Typically, CAR T-cells incorporate a potent constitutive promoter that maximizes long-term CAR expression but extended CAR activation may also promote T-cell exhaustion. Hypoxia-inducible elements can be incorporated to conditionally drive CAR expression and selectively target MM cells within bone marrow. CAR T-cell survival and activity is further realized by blocking intrinsic regulators of T-cell inactivation. T-Cells Redirected for Universal Cytokine Killing (TRUCKs) bind a specific tumor antigen and produce cytokines to recruit endogenous immune cells. Suicide genes have been engineered into CAR T-cells given the potential for long-term on-target, off-tumor effects. Universal allo-CAR T-cells represent an off-the-shelf source, while logic-gated CAR T-cells are designed to recognize tumor-specific features coupled with Boolean-generated binary gates that then dictate cell-fate decisions. Future generations of CARs should further revitalize immune responses, enhance tumor specificity and reimagine strategies to treat myeloma and other cancers.<\/jats:p>","DOI":"10.3389\/fimmu.2022.957157","type":"journal-article","created":{"date-parts":[[2022,8,9]],"date-time":"2022-08-09T04:53:34Z","timestamp":1660020814000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":14,"title":["Road testing new CAR design strategies in multiple myeloma"],"prefix":"10.3389","volume":"13","author":[{"given":"Priyanka S.","family":"Rana","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elena V.","family":"Murphy","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jeries","family":"Kort","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"James 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