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Preventing Lck Activation in CAR T Cells Confers Treg Resistance but Requires 4-1BB Signaling for Them to Persist and Treat Solid Tumors in Nonlymphodepleted Hosts.

Publication ,  Journal Article
Suryadevara, CM; Desai, R; Farber, SH; Choi, BD; Swartz, AM; Shen, SH; Gedeon, PC; Snyder, DJ; Herndon, JE; Healy, P; Reap, EA; Archer, GE ...
Published in: Clin Cancer Res
January 1, 2019

PURPOSE: Chimeric antigen receptor (CAR) T cells have shown promise against solid tumors, but their efficacy has been limited, due in part, to immunosuppression by CD4+FoxP3+ regulatory T cells (Tregs). Although lymphodepletion is commonly used to deplete Tregs, these regimens are nonspecific, toxic, and provide only a narrow window before Tregs repopulate hosts. Importantly, CARs have also been shown to inadvertently potentiate Tregs by providing a source of IL2 for Treg consumption. We explored whether disruption of the IL2 axis would confer efficacy against solid tumors without the need for lymphodepletion. EXPERIMENTAL DESIGN: We developed second- (CD28z) and third- (CD28-4-1BBz) generation CARs targeting EGFRvIII. To eliminate secretion of IL2, 2 amino acid substitutions were introduced in the PYAP Lck-binding motif of the CD28 domain (ΔCD28). We evaluated CARs against B16 melanomas expressing EGFRvIII. RESULTS: CD28z CARs failed to engraft in vivo. Although 4-1BB addition improved expansion, CD28-4-1BBz CARs required lymphodepletion to treat solid tumors. CARs deficient in Lck signaling, however, significantly retarded tumor growth without a need for lymphodepletion and this was dependent on inclusion of 4-1BB. To evaluate CAR vulnerability to Tregs, we lymphodepleted mice and transferred CARs alone or with purified Tregs. Cotransfer with Tregs abrogated the efficacy of CD28-4-1BBz CARs, whereas the efficacy of ΔCD28-4-1BBz CARs remained unperturbed. CONCLUSIONS: In the absence of lymphodepletion, CARs targeting solid tumors are hindered by Treg immunosuppression and poor persistence. Here, CARs were modified to circumvent Treg suppression and to simultaneously improve in vivo engraftment. Modified CARs treated solid tumors without a need for lymphodepletion.

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Published In

Clin Cancer Res

DOI

EISSN

1557-3265

Publication Date

January 1, 2019

Volume

25

Issue

1

Start / End Page

358 / 368

Location

United States

Related Subject Headings

  • Tumor Necrosis Factor Receptor Superfamily, Member 9
  • T-Lymphocytes, Regulatory
  • Signal Transduction
  • Receptors, Chimeric Antigen
  • Oncology & Carcinogenesis
  • Neoplasms
  • Mice
  • Interleukin-2
  • Immunotherapy, Adoptive
  • Humans
 

Citation

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Suryadevara, C. M., Desai, R., Farber, S. H., Choi, B. D., Swartz, A. M., Shen, S. H., … Sanchez-Perez, L. (2019). Preventing Lck Activation in CAR T Cells Confers Treg Resistance but Requires 4-1BB Signaling for Them to Persist and Treat Solid Tumors in Nonlymphodepleted Hosts. Clin Cancer Res, 25(1), 358–368. https://doi.org/10.1158/1078-0432.CCR-18-1211
Suryadevara, Carter M., Rupen Desai, S Harrison Farber, Bryan D. Choi, Adam M. Swartz, Steven H. Shen, Patrick C. Gedeon, et al. “Preventing Lck Activation in CAR T Cells Confers Treg Resistance but Requires 4-1BB Signaling for Them to Persist and Treat Solid Tumors in Nonlymphodepleted Hosts.Clin Cancer Res 25, no. 1 (January 1, 2019): 358–68. https://doi.org/10.1158/1078-0432.CCR-18-1211.
Suryadevara CM, Desai R, Farber SH, Choi BD, Swartz AM, Shen SH, et al. Preventing Lck Activation in CAR T Cells Confers Treg Resistance but Requires 4-1BB Signaling for Them to Persist and Treat Solid Tumors in Nonlymphodepleted Hosts. Clin Cancer Res. 2019 Jan 1;25(1):358–68.
Suryadevara, Carter M., et al. “Preventing Lck Activation in CAR T Cells Confers Treg Resistance but Requires 4-1BB Signaling for Them to Persist and Treat Solid Tumors in Nonlymphodepleted Hosts.Clin Cancer Res, vol. 25, no. 1, Jan. 2019, pp. 358–68. Pubmed, doi:10.1158/1078-0432.CCR-18-1211.
Suryadevara CM, Desai R, Farber SH, Choi BD, Swartz AM, Shen SH, Gedeon PC, Snyder DJ, Herndon JE, Healy P, Reap EA, Archer GE, Fecci PE, Sampson JH, Sanchez-Perez L. Preventing Lck Activation in CAR T Cells Confers Treg Resistance but Requires 4-1BB Signaling for Them to Persist and Treat Solid Tumors in Nonlymphodepleted Hosts. Clin Cancer Res. 2019 Jan 1;25(1):358–368.

Published In

Clin Cancer Res

DOI

EISSN

1557-3265

Publication Date

January 1, 2019

Volume

25

Issue

1

Start / End Page

358 / 368

Location

United States

Related Subject Headings

  • Tumor Necrosis Factor Receptor Superfamily, Member 9
  • T-Lymphocytes, Regulatory
  • Signal Transduction
  • Receptors, Chimeric Antigen
  • Oncology & Carcinogenesis
  • Neoplasms
  • Mice
  • Interleukin-2
  • Immunotherapy, Adoptive
  • Humans