PMID- 36016950
OWN - NLM
STAT- MEDLINE
DCOM- 20220829
LR  - 20220829
IS  - 1664-3224 (Electronic)
IS  - 1664-3224 (Linking)
VI  - 13
DP  - 2022
TI  - Road testing new CAR design strategies in multiple myeloma.
PG  - 957157
LID - 10.3389/fimmu.2022.957157 [doi]
LID - 957157
AB  - A deeper understanding of basic immunology principles and advances in 
      bioengineering have 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.
CI  - Copyright (c) 2022 Rana, Murphy, Kort and Driscoll.
FAU - Rana, Priyanka S
AU  - Rana PS
AD  - Division of Hematology & Oncology, Department of Medicine, Case Western Reserve 
      University, Cleveland, OH, United States.
FAU - Murphy, Elena V
AU  - Murphy EV
AD  - Department of Biochemistry, Case Western Reserve University, Cleveland, OH, 
      United States.
FAU - Kort, Jeries
AU  - Kort J
AD  - Division of Hematology & Oncology, Department of Medicine, Case Western Reserve 
      University, Cleveland, OH, United States.
AD  - Case Comprehensive Cancer Center, School of Medicine, Case Western Reserve 
      University, Cleveland, OH, United States.
FAU - Driscoll, James J
AU  - Driscoll JJ
AD  - Division of Hematology & Oncology, Department of Medicine, Case Western Reserve 
      University, Cleveland, OH, United States.
AD  - Case Comprehensive Cancer Center, School of Medicine, Case Western Reserve 
      University, Cleveland, OH, United States.
LA  - eng
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PT  - Review
DEP - 20220809
PL  - Switzerland
TA  - Front Immunol
JT  - Frontiers in immunology
JID - 101560960
RN  - 0 (CD28 Antigens)
RN  - 0 (Cytokines)
RN  - 0 (Receptors, Antigen, T-Cell)
RN  - 0 (Receptors, Chimeric Antigen)
SB  - IM
MH  - CD28 Antigens
MH  - Cytokines
MH  - Humans
MH  - Immunotherapy, Adoptive
MH  - *Multiple Myeloma/genetics/therapy
MH  - Receptors, Antigen, T-Cell
MH  - *Receptors, Chimeric Antigen
PMC - PMC9395635
OTO - NOTNLM
OT  - CAR T-cell therapy
OT  - armored CAR
OT  - hypoxia
OT  - logic-gates
OT  - multiple myeloma
OT  - self-driving CAR
COIS- The authors state that the manuscript was prepared without any commercial or 
      financial relationships and without any conflict of interest.
EDAT- 2022/08/27 06:00
MHDA- 2022/08/30 06:00
PMCR- 2022/01/01
CRDT- 2022/08/26 02:23
PHST- 2022/05/30 00:00 [received]
PHST- 2022/07/20 00:00 [accepted]
PHST- 2022/08/26 02:23 [entrez]
PHST- 2022/08/27 06:00 [pubmed]
PHST- 2022/08/30 06:00 [medline]
PHST- 2022/01/01 00:00 [pmc-release]
AID - 10.3389/fimmu.2022.957157 [doi]
PST - epublish
SO  - Front Immunol. 2022 Aug 9;13:957157. doi: 10.3389/fimmu.2022.957157. eCollection 
      2022.