T cells redirected against CD70 for the immunotherapy of CD70-positive malignancies

Abstract

IntroductionImmunotherapy with antigen-specific T cells has shown promise in the treatment of hematologic malignancies in preclinical models and in phase 1/2 clinical studies. [1][2][3] One attractive strategy to generate tumor-specific T cells is by genetic modification with chimeric antigen receptors (CARs), which consist of an extracellular antigen-recognition domain, a transmembrane domain, and an intracellular signaling domain derived from the TCR CD3-chain often linked to costimulatory molecule endodomains. 4,5 CARs targeting CD19 and CD20 antigens for the treatment of hematologic malignancies have been explored extensively, but this approach is limited to B cell-derived malignancies and may produce prolonged impairment of humoral immunity because of the potentially long life span of T cells. 6,7 It is therefore desirable to prepare CARs directed against alternative antigens that could broaden the spectrum of potentially treatable tumors and/or potentially reduce damage to normal cells.CD70 is the membrane-bound ligand of the CD27 receptor, which belongs to the tumor necrosis factor receptor superfamily. 8,9 CD70 is expressed by diffuse large B-cell and follicular lymphoma and also by the malignant cells of Hodgkin lymphoma, Waldenström macroglobulinemia, and multiple myeloma, and by human T-lymphotropic virus type 1-and EBV-associated malignancies. [10][11][12][13][14] In addition, CD70 is expressed by nonhematologic malignancies such as renal cell carcinoma and glioblastoma. 15,16 Physiologically, CD70 expression is transient and restricted to a subset of highly activated T, B, and dendritic cells. Whereas CD70/CD27 costimulation plays a role in T-cell activation, CD70/ CD27 signaling is not essential for the development and maintenance of a functional immune system, because CD27-knockout mice have no overt immunodeficiency and recover from influenza virus infection within the same time frame as wild-type mice. 17,18 Targeting CD70-positive malignancies with CD70-specific monoclonal antibodies has shown promise in preclinical animal models, 14,19,20 and we have now evaluated whether T cells can be redirected to CD70 by forced expression of the appropriate CAR. Because CARs consist of an extracellular antigen-recognition domain derived from murine monoclonal antibodies, they may induce human anti-mouse antibody on infusion unless fully humanized. 21,22 One potential strategy to overcome this limitation is to engineer the antigen-recognition domain using endogenous protein ligands or receptors rather than monoclonal antibodies. 23,24 To target CD70 with T cells, we took advantage of the physiologic CD70/CD27 interaction and generated a CD70-specific CAR, which consists of full-length CD27 as the antigen-recognition domain fused to the intracellular domain of the CD3-chain. Engagement of chimeric CD27-by tumor targets expressing the CD70 ligand resulted in T-cell activation and CD27 costimulation, which was dependent on the presence of the TRAF2-binding site within the cytoplasmic tail of CD27. CD70-specifi...

Treatment of Advanced Leukemia in Mice with mRNA Engineered T Cells

“…We chose a dose of 2.5 · 10 7 instead of 10 7 cells by hypothesizing that, as the receptor expression was selflimited to a few days, the CAR-driven expansion of cells would similarly be limited and a higher starting cell dose might be required to demonstrate efficacy in a high tumor burden. Preclinical models using stably transduced CD19 CAR + T cells with retroviruses have used a schedule of three or four separate injections with 3-4 · 10 7 total T cells in similar models (Brentjens et al, 2007;Shaffer et al, 2011). We were surprised to observe a 2-log reduction of bioluminescent signal as early as 24 hr after injection, a reduction that was sustained over time ( p < 0.01; Fig.…”

Chimeric antigen receptor T-cell therapies for multiple myeloma

“…64 CD70 is under investigation as a CAR target. 65,66 Although CD70 might be a good target for some malignancies, the suitability of targeting CD70 in MM is unclear as it has been reported to not be uniformly expressed by the malignant plasma cells in most cases of MM.…”

Immunotherapy for B-Cell Neoplasms Using T-Cells Expressing Chimeric Antigen Receptors : From Antigen Choice to Clinical Implementation

“…Other CARtargeting CD22 (CART22), CD23 (CART23), and CD70 (CART70) antigens as well as κ LC (CARTκ) were also developed showing promising results in in vitro and in vivo mouse tumour models. [57][58][59][60] With respect to the therapeutic potential of tested CAR, it is worthwhile to note that suboptimal cytotoxic effects of these genetically engineered T cells vary among targeted antigens. Although several explanations may be proposed, one possible reason is the difference in expression levels of the targeted antigens in malignant and normal B cells.…”