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Poster Discussion 1 – Immunotherapy of cancer

4379 - Results of a phase I trial with MART-1 T cell receptor modified T cells in patients with metastatic melanoma

Date

28 Sep 2019

Session

Poster Discussion 1 – Immunotherapy of cancer

Presenters

Maartje Rohaan

Citation

Annals of Oncology (2019) 30 (suppl_5): v475-v532. 10.1093/annonc/mdz253

Authors

M.W. Rohaan1, R. Gomez-Eerland2, M.H. Geukes Foppen1, M. van Zon3, R. de Boer3, N.A.M. Bakker3, L.M. Pronk4, A. Sari4, H.A. Mallo1, B.A. van de Wiel5, F. Lalezari6, J.H. Beijnen7, B. Nuijen7, H. van Tinteren4, J.V. van Thienen1, C.U. Blank1, S. Wilgenhof1, T.N. Schumacher2, J.H. van den Berg3, J.B.A.G. Haanen1

Author affiliations

  • 1 Medical Oncology, Netherlands Cancer Institute/Antoni van Leeuwenhoek hospital (NKI-AVL), 1066 CX - Amsterdam/NL
  • 2 Molecular Oncology And Immunology, Netherlands Cancer Institute/Antoni van Leeuwenhoek hospital (NKI-AVL), 1066 CX - Amsterdam/NL
  • 3 Biotherapeutics Unit, Netherlands Cancer Institute/Antoni van Leeuwenhoek hospital (NKI-AVL), 1066 CX - Amsterdam/NL
  • 4 Biometrics, Netherlands Cancer Institute/Antoni van Leeuwenhoek hospital (NKI-AVL), 1066 CX - Amsterdam/NL
  • 5 Pathology, Netherlands Cancer Institute/Antoni van Leeuwenhoek hospital (NKI-AVL), 1066 CX - Amsterdam/NL
  • 6 Radiology, Netherlands Cancer Institute/Antoni van Leeuwenhoek hospital (NKI-AVL), 1066 CX - Amsterdam/NL
  • 7 Pharmacy And Pharmacology, Netherlands Cancer Institute/Antoni van Leeuwenhoek hospital (NKI-AVL), 1066 CX - Amsterdam/NL

Resources

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Abstract 4379

Background

Adoptive cell therapy (ACT) with T cell receptor (TCR) gene modified peripheral blood T cells creates large pools of tumor reactive T cells. Based on preclinical validation we have selected a high affinity MART-1-specific TCR for TCR gene therapy in metastatic melanoma (MM). Utilizing a novel GMP production protocol we performed a phase I trial to asses feasibility, safety and efficacy of TCR gene therapy in pts with MM.

Methods

HLA-A2*0201+ pts with irresectable stage IIIc/IV melanoma, expressing MART-1 and MHC class I, with no standard treatment options were included. Autologous T cells were isolated via apheresis and transduced with a MP-71 retroviral vector encoding the 1D3HMCys MART-1 TCR and expanded ex vivo in presence of IL-7 and IL-15. Non-myeloablative chemotherapy was given prior to one i.v. infusion of MART-1 TCR transduced T cells in a dose escalating manner after evaluation of adverse events (AEs). Feasibility, safety (CTCAE 4.0) and ORR (RECIST 1.1) were assessed.

Results

Twelve heavily pretreated metastatic cutaneous (n = 7) and uveal (n = 5) melanoma (mUM) pts were treated with MART-1 TCR transduced T cells across 4 dose cohorts. Transduction efficiency was 42-76%. Viability of the cell product was 92.9-98.5%. Pt 1 received 4.56 x 109 MART-1 TCR transduced T cells but died 9 days post infusion due to multiple organ failure. Subsequent pts received 5 x 107 (n = 3; cohort (c) 2), 25 x 107 (n = 2; c3) and 10 x 107 (n = 6; c4) cells. On-target AEs were dose-dependent and included dermatitis (10/11) max grade 3, uveitis (3/11) max grade 2 and ototoxicity (4/11) max grade 3, highest in cohort 3. Four pts (n = 2 c3; n = 2 c4) showed signs of cytokine release syndrome and 3 pts required tocilizumab. Objective PR by RECIST 1.1 was seen in 2 pts (17%), with a DOR of 4.2 (mUM, c4) and 8.4 (c3) months. Persistence of transduced T cells in peripheral blood was correlated with infused cell dose.

Conclusions

Treatment with MART-1 TCR transduced peripheral blood T cells expanded in presence of IL-7 and IL-15 led to severe dose-dependent toxicity with a maximum tolerated dose of 10 x 107 transduced cells. Despite observed responses, toxicity limited further development and use of this MART-1 TCR cellular therapy in MM patients. NCT02654821.

Clinical trial identification

NCT02654821.

Editorial acknowledgement

Legal entity responsible for the study

Netherlands Cancer Institute/Antoni van Leeuwenhoek hospital (NKI-AVL).

Funding

KWF Kankerbestrijding.

Disclosure

J.H. Beijnen: Shareholder / Stockholder / Stock options, Full / Part-time employment: Modra Pharmaceuticals BV . J.V. van Thienen: Honoraria (institution), Advisory / Consultancy: Pfizer ; Honoraria (institution), Advisory / Consultancy: Novartis. C.U. Blank: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): BMS; Honoraria (self), Advisory / Consultancy: MSD; Honoraria (self), Advisory / Consultancy: Roche; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Novartis; Honoraria (self), Advisory / Consultancy: Lilly; Honoraria (self), Advisory / Consultancy: Pfizer; Honoraria (self), Advisory / Consultancy: GSK; Honoraria (self), Advisory / Consultancy: GenMab; Honoraria (self), Advisory / Consultancy: Pierre Fabre ; Research grant / Funding (institution): NanoString. T.N. Schumacher: Advisory / Consultancy: Adaptive Biotechnologies; Advisory / Consultancy, Shareholder / Stockholder / Stock options: AIMM Therapeutics; Advisory / Consultancy, Shareholder / Stockholder / Stock options: Allogene Therapeutics; Advisory / Consultancy: Amgen; Advisory / Consultancy, Shareholder / Stockholder / Stock options: Merus; Advisory / Consultancy, Shareholder / Stockholder / Stock options: Neon Therapeutics; Advisory / Consultancy: Scenic Biotech; Advisory / Consultancy: Third Rock Ventures; Research grant / Funding (institution): Merck; Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution): Merck KGaA; Shareholder / Stockholder / Stock options: Neogene Therapeutics; Shareholder / Stockholder / Stock options: Scenic Biotech. J.B.A.G. Haanen: Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution): BMS; Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution): MSD; Honoraria (institution), Advisory / Consultancy: Pfizer; Honoraria (institution), Advisory / Consultancy: AZ/MedImmune; Honoraria (institution), Advisory / Consultancy: Roche/Genentech; Honoraria (institution), Advisory / Consultancy: Ipsen; Honoraria (institution), Advisory / Consultancy: Bayer; Honoraria (institution), Advisory / Consultancy: Immunocore; Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution): Novartis; Honoraria (institution), Advisory / Consultancy: Seattle Genetics; Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution): Neon Therapeutics; Honoraria (institution), Advisory / Consultancy: Celsius Therapeutics; Honoraria (institution), Advisory / Consultancy: Gadet ; Honoraria (institution), Advisory / Consultancy: GSK. All other authors have declared no conflicts of interest.

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