Melanoma-associated chondroitin sulfate proteoglycan (MCSP) as target antigen for specific immunotherapy; from the bench to the bed-side.
Final Report Abstract
The overall emphasis of our joint trilateral project was the improvement of T-cell-based immunotherapy of melanoma, focusing on the use of melanoma-associated chondroitin sulfate proteoglycan (MCSP). Due to the high success rates of double immune checkpoint blockade in skin melanoma, we decided to switch our focus to melanoma of the eye (uveal melanoma; UM). UM is an orphan disease with a very poor prognosis as soon as metastases arise. MCSP is also expressed in uveal melanoma, and we, therefore, predict the effectiveness of our MCSP-CAR-T cells in these patients. We showed that the repeated production of a sufficient number of highly pure MCSP-CAR-transfected T cells with high potency to kill melanoma target cells is feasible. The GMP-compliant CAR-T-cell-production process was successfully assessed by the Bavarian government, and official production approval was issued in 2020. A fruitful scientific advice meeting with the Federal Institute for Vaccines and Biomedicines (Paul-Ehrlich-Institute (PEI)) was held, and we are now finishing the mandatory documentation as a final step before submitting the proposed MCSP-CAR-T-cell clinical trial to PEI, which will be financed through other sources. However, we were not able to start the clinical trial yet (due to delays caused by the Corona pandemic and shortage of funding). SLAMF6 is a highly potent immune checkpoint for cancer immunotherapy that was not recognized as such because of its dual signaling pattern that results from two molecular forms (splice isoforms), a short and a long one, with opposite effects. We have focused our efforts on the dominant-positive agonist. Using various technologies and a series of in vitro and in vivo studies, the major discovery of our project has been that the SLAMF6 agonist can augment the efficacy of adoptive cell therapies. Another goal of our study was to decipher the molecular partners associated with SLAMF6 to elucidate its role in the immune cascade and its effect on other receptors. As a continuation of the collaboration with the Erlangen partner, we established a consortium in the Horizon Health 2021 program of the European Union project "CanceRNA". In the frame of this consortium, we expect to develop a technology that has the potential to become of paramount importance in treating cancer and other diseases, including autoimmunity and inborn errors of immunity. The use of immunohistochemistry (IHC) biomarkers has significantly improved the prognostic impact on oncological practices and patient care, as it plays a role in the selection of immunotherapy strategies in cancer patients. A study was done on 25 patients who received Nivolumab incorporated the use of IHC for PD-L1 and suggested that those that were positive for PD-L1 demonstrated an objective response to the drug, while PD-L1 negative patients did not. In our study, an immunoscore was established for five different proteins: CD155, MCSP, PD-L1, Galectin-9, and IL-2Rβ. After performing the IHC protocol on 22 cell lines, PD-L1 was the only one that showed a significant correlation with the overall and 2-year progression-free survival of the patients. Additionally, the total exonic mutation burden identified using small gene panels can predict immunotherapy responses. In a study of 65 melanoma patients, mutation burden calculated using FoundationOne (315 genes) was considerably associated with treatment response and survival, particularly at >20 mutations/Mb. Our group has tested a small cohort of cutaneous melanoma patients using the Trusight Oncology 500 panel with the aim of identifying the landscape of mutations in cutaneous melanoma. Our analysis showed that all samples were high in exonic mutation burden ranging from ~5-48 mutations per Mb.
Publications
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Clinical-Scale Production of CAR-T Cells for the Treatment of Melanoma Patients by mRNA Transfection of a CSPG4-Specific CAR under Full GMP Compliance. Cancers (Basel). 2019 Aug 16;11(8):1198
Wiesinger M, März J, Kummer M, Schuler G, Dörrie J, Schuler-Thurner B, Schaft N
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CSPG4 as Target for CAR-T-Cell Therapy of Various Tumor Entities-Merits and Challenges. Int J Mol Sci. 2019 Nov 26;20(23):5942
Harrer DC, Dörrie J, Schaft N
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CSPG4-Specific CAR T Cells for High-Risk Childhood B Cell Precursor Leukemia. Int J Mol Sci. 2019 Jun 5;20(11):2764
Harrer DC, Schuler G, Dörrie J, Schaft N
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CARs: Beyond T Cells and T Cell-Derived Signaling Domains. Int J Mol Sci. 2020 May 15;21(10):3525
Sievers NM, Dörrie J, Schaft N
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SLAMF6 deficiency augments tumor killing and skews toward an effector phenotype revealing it as a novel T cell checkpoint. Elife. 2020 Mar 3;9:e52539
Hajaj E, Eisenberg G, Klein S, Frankenburg S, Merims S, Ben David I, Eisenhaure T, Henrickson SE, Villani AC, Hacohen N, Abudi N, Abramovich R, Cohen JE, Peretz T, Veillette A, Lotem M
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The Landscape of CAR-T Cell Clinical Trials against Solid Tumors-A Comprehensive Overview. Cancers (Basel). 2020 Sep 9;12(9):2567
Schaft N.
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Alternative Splicing of the Inhibitory Immune Checkpoint Receptor SLAMF6 Generates a Dominant Positive Form, Boosting T-cell Effector Functions. Cancer Immunol Res. 2021 Jun;9(6):637-650
Hajaj E, Zisman E, Tzaban S, Merims S, Cohen J, Klein S, Frankenburg S, Sade- Feldman M, Tabach Y, Yizhak K, Navon A, Stepensky P, Hacohen N, Peretz T, Veillette A, Karni R, Eisenberg G, Lotem M
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Decitabine-Mediated Upregulation of CSPG4 in Ovarian Carcinoma Cells Enables Targeting by CSPG4-Specific CAR-T Cells. Cancers (Basel). 2022, 14, 5033
Harrer DC, Schenkel C, Berking C, Herr W, Abken H, Dörrie J, Schaft N
