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2020-02-25T14:36:33.000Z

Third-generation CAR-CD30 T-cell therapy for CD30-positive lymphomas

Feb 25, 2020
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The two currently approved chimeric antigen receptor (CAR) T-cell therapies for the treatment of relapsed/refractory (R/R) large B-cell lymphoma (LBCL) — axicabtagene ciloleucel and tisagenlecleucel — have demonstrated significant clinical benefit in patients with R/R disease.1,2 These CAR T-cell therapies are CD19-directed, but other types of lymphoma, such as classical Hodgkin lymphoma (cHL) and anaplastic large cell lymphoma (ALCL), lack CD19 expression and so alternative CAR T-cell-based therapies are required.3

CD30 is a cell membrane protein and a member of the tumor necrosis factor receptor superfamily which has been identified as an attractive target for CAR T-cell therapy. This is due to its expression on most cHLs and ALCLs, as well as in a proportion of other lymphomas, such as cutaneous T-cell lymphomas (CTCLs) and diffuse LBCLs (DLBCLs).4

CD30 is a target of a number of antibody-based therapies. Most notably, positive results have been achieved with brentuximab vedotin (BV), an antibody drug conjugate targeting CD30+ cells, which is approved by the EMA for the treatment of cHL, ALCL, and CTCL.5 However, there are limitations associated with BV treatment, such as inadequate persistence and tumor penetration. Consequently, anti-CD30 CAR T cells are being investigated for the treatment of CD30+ lymphomas.4

Thus far, two phase I/II clinical trials (NCT01316146 and NCT02259556) have investigated the potential use of anti-CD30 CAR T-cell therapy in R/R cHL or ALCL. Despite small cohort sizes, the two trials reported tolerable CD30 CAR T-cell regimens, however clinical benefit was sub-optimal.6–8 Preclinical advances of a third-generation, anti-CD30 CAR T-cell therapy were presented by Biagio De Angelis, Bambino Gesù Pediatric Hospital, IRCCS, Rome, IT, at the 2nd European CAR T Cell Meeting.3 The data are based on results previously shown at the  61st ASH Annual Meeting & Exposition in Orlando, US.8

Study design9

  • A comparative preclinical study evaluating the stability and anti-tumor activity of two CD30 CAR-T constructs

CAR design3

  • A third-generation CAR construct containing an anti-CD30 single-chain variable-fragment cassette linked to CD3ζ by the signaling domains of either:
    • CD28.4-1BB

or

    • CD28.OX40
  • The vector incorporates an inducible caspase-9 (iCasp9) suicide gene
  • A CD34 antibody recognition domain was incorporated in the hinge region of all vectors as a selection marker

Methods9

  • In vitro anti-tumor efficacy was evaluated using non-Hodgkin lymphoma (Karpas299) and cHL (L428) cell lines, a short-term cytotoxic assay (51Cr release assay), and long-term co-cultures
    • Supernatant from co-culture experiments was analyzed by enzyme-linked immunosorbent assays (ELISA)
  • In vivo NSG mouse models were engrafted i.v. with lymphoma FF-luciferase cell lines, Karpas299 or L428
  • In vivo tumor growth was monitored using bioluminescent imaging
  • Tumor re-challenging was initiated by i.v. infusion of 0.2x106 Karpas299 cells into mice that survived until Day +140 and were observed for an additional 110 days

Results8,9

  • High transduction rates were obtained with all constructs (80–90%)
  • Insertion of a CD34 antigen allowed for convenient selection and monitoring of transduced cells
  • Introduction of the iCasp9 suicide gene allowed controlled apoptosis of CD30 CAR T cells, irrespective of their co-stimulatory domains
  • Incorporation of a CD28.OX40 vs CD28.4-1BB costimulatory domain into a CD30-CAR resulted in a more stable CAR expression 30 days after transduction (84.72 ± 5.30% vs 63.98 ± 11.51; p = 0.002)
  • CAR CD30-CD28.OX40 elicited greater anti-lymphoma properties in comparison to CAR CD30-CD28.4-1BB in vitro
    • The level of IFNγ (pg/ml/1e6) T cells was significantly higher in CD30-CD28.OX40 vs CD30-CD28.4-1BB transfected T cells
    • In long-term co-culture experiments with various cell lines, CD28.OX40 CD30 CAR T cells showed significantly higher anti-lymphoma activity compared to CD28.41BB CAR T cells when challenged at high tumor/effector ratio
    • Secretion of Th1 cytokines (IFNγ, IL-2, and TNFα) after antigen stimulation was significantly higher in CD30-CD28.OX40 vs CD30-CD28.4-1BB transfected T cells (p = 0.040, p = 0.008, and p = 0.02, respectively)
  • At the experimental endpoint (Day +165), overall survival was significantly improved in CD30-CD28.OX40 vs CD30-CD28.4-1BB CAR T-cell-treated mice (60% vs 0%), p = 0.0021
  • Persistence of CD28.OX40 CAR T-cell established long-term immunological memory as demonstrated by second tumor challenge experiments in mouse tumor models

Conclusions3

  • The iCasp9 system stands as a promising approach to decrease toxicities across CAR T-cell therapies
  • The CD30-CD28.OX40 CAR construct could overcome the limited efficacy of previously investigated CD30 CAR T-cell therapies in CD30+ lymphomas if the preclinical data translates to clinical studies

How can third generation anti-CD30 CARs improve treatment of CD30+ lymphomas?

  1.  S. Food and Drug Administration. YESCARTA (axicabtagene ciloleucel). Available at: https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/yescarta-axicabtagene-ciloleucel. [Accessed Feb 7, 2020]
  2.  S. Food and Drug Administration. KIMRIAH (tisagenlecleucel) . Available at: https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/kymriah-tisagenlecleucel. [Accessed February 7, 2020]
  3.  De Angelis B. A new promising third generation CAR-CD30 T-cell therapy for CD30+ lymphoma. 2020 Jan 30: 2nd European CAR T cell Meeting, Sitges, ES
  4.  Grover N.S. et al. Challenges of driving CD30-directed CAR-T-cells to the clinic. BMC Cancer.  2019 Mar 6; 19:203. DOI: https://doi.org/10.1186/s12885-019-5415-9
  5.  European Medicines Agency. Adcetris, brentuximab vedotin. Available at: https://www.ema.europa.eu/en/medicines/human/EPAR/adcetris. [Accessed February 19, 2020]
  6. Ramos C.A. et al. Clinical and immunological responses after CD30-specific chimeric antigen receptor-redirected lymphocytes. J Clin Invest.2017 Sep 1; 127(9):3462–3471. DOI: 1172/JCI94306
  7.  Wang C.M. Autologous T-cells expressing CD30 chimeric antigen receptors for relapsed or refractory Hodgkin lymphoma: An open-label phase I trial. Clin Cancer Res.2017 Mar 1; 23(5):1156–1166. DOI: 1158/1078-0432.CCR-16-1365
  8. De Angelis B. et al. A new promising third generation CAR-CD30 T-cell therapy for CD30+ lymphoma. Blood. 2019 Nov 13; 134(Supplement_1):2069. DOI: https://doi.org/10.1182/blood-2019-127969
  9.  De Angelis B. et al. A new promising third generation CAR-CD30 T-cell therapy for CD30+ lymphoma. Poster presented at:61st American Society of Hematology (ASH) Meeting & Exposition; 2019 Dec; Orlando, US


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