Chimeric receptors containing CD137 signal transduction domains mediate enhanced survival of T cells and increased anti-leukemic efficacy in vivo

By M. Milone, J. Fish, C. Carpenito, R. Carroll, Gwendolyn K. Binder, D. Teachey, M. Samanta, M. Lakhal, Brian S. Gloss, G. Danet-Desnoyers and 4 more. Molecular Therapy, 2009

1,165 citations recorded by the source corpus.

Persistence of T cells engineered with chimeric antigen receptors (CARs) has been a major barrier to use of these cells for molecularly targeted adoptive immunotherapy. To address this issue, we created a series of CARs that contain the TCR-ζ signal transduction domain with the CD28 and/or CD137 (4-1BB) intracellular domains in tandem. After short-term expansion, primary human T cells were subjected to lentiviral gene transfer, resulting in large numbers of cells with >85% CAR expression. In an immunodeficient mouse xenograft model of primary human pre-B-cell acute lymphoblastic leukemia, human T cells expressing anti-CD19 CARs containing CD137 exhibited the greatest anti-leukemic efficacy and prolonged (>6 months) survival in vivo, and were significantly more effective than cells expressing CARs containing TCR-ζ alone or CD28-ζ signaling receptors. We uncovered a previously unrecognized, antigen-independent effect of CARs expressing the CD137 cytoplasmic domain that likely contributes to the enhanced antileukemic efficacy and survival in tumor bearing mice. Furthermore, our studies revealed significant discrepancies between in vitro and in vivo surrogate measures of CAR efficacy. Together these results suggest that incorporation of the CD137 signaling domain in CARs should improve the persistence of CARs in the tumor microenvironment and hence maximize their antitumor activity.

Subfields: Genetics, Molecular Biology, Oncology

View Paper: https://www.semanticscholar.org/paper/7b0f45faccc8f61a08b84288c6fcb625c0214a6c

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In Genetics

1. C. June
2. S. Grupp
3. Wendell A. Lim
4. Michel Sadelain
5. D. Porter
6. B. Levine
7. S. Maude
8. D. Teachey

In Molecular Biology

1. C. June
2. Wendell A. Lim
3. Dimiter S. Dimitrov
4. B. Keith
5. Michel Sadelain
6. K. Davis

In Oncology

1. C. June
2. Michel Sadelain
3. Wendell A. Lim
4. J. Kochenderfer
5. S. Grupp
6. R. Brentjens
7. S. Maude
8. D. Porter

Citations in the corpus

• CD19-targeted T cells rapidly induce molecular remissions in adults with chemotherapy-refractory acute lymphoblastic leukemia (2013, background): “(7) reported similar therapeutic efficacy of CD28/CD3z and 4-1BB/ CD3z T cells in treating CD19 leukemia, with the latter accumulating to higher levels in delayed fashion.”
• Efficacy and Toxicity Management of 19-28z CAR T Cell Therapy in B Cell Acute Lymphoblastic Leukemia (2014, methodology): “Accordingly, the persistence of CD19-targeted CARs incorporating a 4-1BB moiety rather than CD28 as used by the University of Pennsylvania may be due, at least in part, to antigen-independent signaling through the 4-1BB CAR, as previously demonstrated in preclinical studies (17).”
• B cell maturation antigen-specific CAR T cells are clinically active in multiple myeloma. (2019, methodology): “One explanation for this difference may be the costimulatory domains used within the 2 CAR constructs, since CD28 domains, such as the one used in the NCI CAR construct, have been associated with more rapid CAR T cell proliferation and cytokine release than 4-1BB domains (29), as used in our CAR con”
• Anti-CD22-chimeric antigen receptors targeting B-cell precursor acute lymphoblastic leukemia. (2013, background): “20 focused on CD137 and CD3-zeta chain only vectors, omitting CD28, reasoning that the IL-2 supplied in tissue culture rendered this signaling unit redundant (34, 35).”
• Chimeric antigen receptor T cells persist and induce sustained remissions in relapsed refractory chronic lymphocytic leukemia (2015, methodology): “Vector production The CD19-BB-z transgene (GeMCRIS 0607-793) was designed and constructed as described (27).”
• Chimeric Antigen Receptor–Modified T Cells in Chronic Lymphoid Leukemia (2011, background): “Cytogenetic analysis showed two separate clones, both resulting in loss of chromosome 17p and the TP53 locus (46,XY,del(17)(p12) [5]/46,XY,der(17)t(17;21)(q10;q10)[5]/46,XY[14]).”
• CD19-targeted chimeric antigen receptor T-cell therapy for acute lymphoblastic leukemia. (2015, background): “Similar antitumor effects are seen in vitro with CD28 or 4-1BB CARs, but preclinical in vivo studies(22) suggest that 4-1BB CARs (Figure 2) may produce superior proliferation and/or persistence.(21,24) Moreover, clinical trials suggest that both of these “second-generation” CARs are capable of induc”
• Distinct Signaling of Coreceptors Regulates Specific Metabolism Pathways and Impacts Memory Development in CAR T Cells. (2016, methodology): “Similarly, the BBz CAR contained the scFv linked to the 4-1BB intracellular portion and the CD3z domain through a CD8a hinge and transmembrane domain (Milone et al., 2009).”
• Tisagenlecleucel in Children and Young Adults with B-Cell Lymphoblastic Leukemia (2018, background): “Increase in aspartate aminotransferase 5 (7) 2 (3) — —”