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CD30-Redirected Chimeric Antigen Receptor T Cells Target CD30+ and CD30- Embryonal Carcinoma via Antigen-Dependent and Fas/FasL Interactions.

ABSTRACT: Tumor antigen heterogeneity limits success of chimeric antigen receptor (CAR) T-cell therapies. Embryonal carcinomas (EC) and mixed testicular germ cell tumors (TGCT) containing EC, which are the most aggressive TGCT subtypes, are useful for dissecting this issue as ECs express the CD30 antigen but also contain CD30-/dim cells. We found that CD30-redirected CAR T cells (CD30.CAR T cells) exhibit antitumor activity in vitro against the human EC cell lines Tera-1, Tera-2, and NCCIT and putative EC stem cells identified by Hoechst dye staining. Cytolytic activity of CD30.CAR T cells was complemented by their sustained proliferation and proinflammatory cytokine production. CD30.CAR T cells also demonstrated antitumor activity in an in vivo xenograft NOD/SCID/?cnull (NSG) mouse model of metastatic EC. We observed that CD30.CAR T cells, while targeting CD30+ EC tumor cells through the CAR (i.e., antigen-dependent targeting), also eliminated surrounding CD30- EC cells in an antigen-independent manner, via a cell-cell contact-dependent Fas/FasL interaction. In addition, ectopic Fas (CD95) expression in CD30+ Fas- EC was sufficient to improve CD30.CAR T-cell antitumor activity. Overall, these data suggest that CD30.CAR T cells might be useful as an immunotherapy for ECs. Additionally, Fas/FasL interaction between tumor cells and CAR T cells can be exploited to reduce tumor escape due to heterogeneous antigen expression or to improve CAR T-cell antitumor activity. Cancer Immunol Res; 6(10); 1274-87. ©2018 AACR.

SUBMITTER: Hong LK

PROVIDER: S-EPMC7590161 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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CD30-Redirected Chimeric Antigen Receptor T Cells Target CD30+ and CD30- Embryonal Carcinoma via Antigen-Dependent and Fas/FasL Interactions.

Hong Lee K LK Chen Yuhui Y Smith Christof C CC Montgomery Stephanie A SA Vincent Benjamin G BG Dotti Gianpietro G Savoldo Barbara B

Cancer immunology research 20180807 10

Tumor antigen heterogeneity limits success of chimeric antigen receptor (CAR) T-cell therapies. Embryonal carcinomas (EC) and mixed testicular germ cell tumors (TGCT) containing EC, which are the most aggressive TGCT subtypes, are useful for dissecting this issue as ECs express the CD30 antigen but also contain CD30-/dim cells. We found that CD30-redirected CAR T cells (CD30.CAR T cells) exhibit antitumor activity in vitro against the human EC cell lines Tera-1, Tera-2, and NCC ...[more]

PMID: 30087115

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Project description:Targeting CD30 with monoclonal antibodies in Hodgkin lymphoma (HL) and anaplastic large cell lymphoma (ALCL) has had profound clinical success. However, adverse events, mainly mediated by the toxin component of the conjugated antibodies, cause treatment discontinuation in many patients. Targeting CD30 with T cells expressing a CD30-specific chimeric antigen receptor (CAR) may reduce the side effects and augment antitumor activity.We conducted a phase I dose escalation study in which 9 patients with relapsed/refractory HL or ALCL were infused with autologous T cells that were gene-modified with a retroviral vector to express the CD30-specific CAR (CD30.CAR-Ts) encoding the CD28 costimulatory endodomain. Three dose levels, from 0.2 × 108 to 2 × 108 CD30.CAR-Ts/m2, were infused without a conditioning regimen. All other therapy for malignancy was discontinued at least 4 weeks before CD30.CAR-T infusion. Seven patients had previously experienced disease progression while being treated with brentuximab.No toxicities attributable to CD30.CAR-Ts were observed. Of 7 patients with relapsed HL, 1 entered complete response (CR) lasting more than 2.5 years after the second infusion of CD30.CAR-Ts, 1 remained in continued CR for almost 2 years, and 3 had transient stable disease. Of 2 patients with ALCL, 1 had a CR that persisted 9 months after the fourth infusion of CD30.CAR-Ts. CD30.CAR-T expansion in peripheral blood peaked 1 week after infusion, and CD30.CAR-Ts remained detectable for over 6 weeks. Although CD30 may also be expressed by normal activated T cells, no patients developed impaired virus-specific immunity.CD30.CAR-Ts are safe and can lead to clinical responses in patients with HL and ALCL, indicating that further assessment of this therapy is warranted.ClinicalTrials.gov NCT01316146.National Cancer Institute (3P50CA126752, R01CA131027 and P30CA125123), National Heart, Lung, and Blood Institute (R01HL114564), and Leukemia and Lymphoma Society (LLSTR 6227-08).

Project description:Chimeric antigen receptors (CARs) are artificial fusion proteins that incorporate antigen-recognition domains and T cell signaling domains. CD30 is a cell surface protein expressed on Hodgkin's lymphoma, some T cell lymphomas, and some B cell lymphomas. CD30 has a restricted expression pattern in normal cells, so CD30 has good potential as a clinical target for CAR T cells. We compared three different anti-CD30 CAR designs incorporating a single-chain variable fragment derived from the 5F11 fully human monoclonal antibody. 5F11-28Z has hinge, transmembrane, and costimulatory domains from CD28 and a CD3ζ T cell activation domain. 5F11-CD828Z has hinge and transmembrane domains from CD8α, a CD28 costimulatory domain, and a CD3ζ T cell activation domain. 5F11-CD8BBZ is identical to 5F11-CD828Z, except for the replacement of the CD28 moiety with a 4-1BB moiety. We found that T cells expressing 5F11-CD8BBZ had lower levels of CD30-specific degranulation and cytokine release compared with CD28-containing CARs. When compared to the CD28-containing CARs, T cells expressing 5F11-CD8BBZ had higher levels of nonspecific functional activity, including degranulation, cytokine release, and proliferation, when stimulated with CD30-negative target cells. We established tumors in nod-scid common gamma-chain deficient (NSG) mice and treated the tumors with T cells expressing different CARs. T cells expressing 5F11-28Z were most effective at eradicating tumors. T cells expressing 5F11-CD828Z had intermediate effectiveness, and T cells expressing 5F11-CD8BBZ were least effective. CD30+ T cells are lost from cultures of T cells containing 5F11-28Z-expressing T cells. This indicated the killing of CD30+ T cells by the 5F11-28Z-expressing T cells. Despite this, the number of T cells in the cultures consistently accumulated to numbers needed for use in a clinical trial. Based on all in vitro and murine experiments comparing the different CARs, we selected 5F11-28Z for further development, and we have initiated a clinical trial testing 5F11-28Z T cells.

Dataset Information

CD30-Redirected Chimeric Antigen Receptor T Cells Target CD30+ and CD30- Embryonal Carcinoma via Antigen-Dependent and Fas/FasL Interactions.

Publications

CD30-Redirected Chimeric Antigen Receptor T Cells Target CD30<sup>+</sup> and CD30<sup>-</sup> Embryonal Carcinoma via Antigen-Dependent and Fas/FasL Interactions.

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