Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
Cancer Immunology, Immunotherapy
Published in: Cancer Immunology, Immunotherapy 4/2018

01-04-2018 | Review

Clinical translation and regulatory aspects of CAR/TCR-based adoptive cell therapies—the German Cancer Consortium approach

Published in: Cancer Immunology, Immunotherapy | Issue 4/2018

Login to get access

Abstract

Adoptive transfer of T cells genetically modified by TCRs or CARs represents a highly attractive novel therapeutic strategy to treat malignant diseases. Various approaches for the development of such gene therapy medicinal products (GTMPs) have been initiated by scientists in recent years. To date, however, the number of clinical trials commenced in Germany and Europe is still low. Several hurdles may contribute to the delay in clinical translation of these therapeutic innovations including the significant complexity of manufacture and non-clinical testing of these novel medicinal products, the limited knowledge about the intricate regulatory requirements of the academic developers as well as limitations of funds for clinical testing. A suitable good manufacturing practice (GMP) environment is a key prerequisite and platform for the development, validation, and manufacture of such cell-based therapies, but may also represent a bottleneck for clinical translation. The German Cancer Consortium (DKTK) and the Paul-Ehrlich-Institut (PEI) have initiated joint efforts of researchers and regulators to facilitate and advance early phase, academia-driven clinical trials. Starting with a workshop held in 2016, stakeholders from academia and regulatory authorities in Germany have entered into continuing discussions on a diversity of scientific, manufacturing, and regulatory aspects, as well as the benefits and risks of clinical application of CAR/TCR-based cell therapies. This review summarizes the current state of discussions of this cooperative approach providing a basis for further policy-making and suitable modification of processes.
Literature
1.
Thomas ED (1975) Bone marrow transplantation: prospects for leukemia and other conditions. Proc Inst Med Chic 30:256–258PubMed
2.
3.
Kolb HJ (2008) Graft-versus-leukemia effects of transplantation and donor lymphocytes. Blood 112:4371–4383CrossRefPubMed
4.
Billingham RE (1966) The biology of graft-versus-host reactions. Harvey Lect 62:21–78PubMed
5.
6.
Schadendorf D, Hodi FS, Robert C et al (2015) Pooled analysis of long-term survival data from phase II and phase III trials of ipilimumab in unresectable or metastatic melanoma. J Clin Oncol 33:1889–1894CrossRefPubMedPubMedCentral
7.
8.
Couzin-Frankel J (2013) Breakthrough of the year 2013. Cancer Immunother Sci 342:1432–1433
9.
10.
11.
Wang X, Popplewell LL, Wagner JR et al (2016) Phase 1 studies of central memory-derived CD19 CAR T-cell therapy following autologous HSCT in patients with B-cell NHL. Blood 127:2980–2990CrossRefPubMedPubMedCentral
12.
Porter DL, Levine BL, Kalos M et al. (2011) Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia. N Engl J Med. 365: 725 – 33
13.
Johnson LA, Morgan RA, Dudley ME et al. (2009) Gene therapy with human and mouse T-cell receptors mediates cancer regression and targets normal tissues expressing cognate antigen. Blood 114: 535–546CrossRefPubMedPubMedCentral
14.
Morgan RA, Dudley ME, Wunderlich JR et al (2006) Cancer regression in patients after transfer of genetically engineered lymphocytes. Science 314:126–129CrossRefPubMedPubMedCentral
15.
Robbins PF, Morgan RA, Feldman SA et al. (2011) Tumor regression in patients with metastatic synovial cell sarcoma and melanoma using genetically engineered lymphocytes reactive with NY-ESO-1. J Clin Oncol. 29: 917–924CrossRefPubMedPubMedCentral
16.
Rapoport AP, Stadtmauer EA, Binder-Scholl GK et al. (2015) NY-ESO-1-specific TCR-engineered T cells mediate sustained antigen-specific antitumor effects in myeloma. Nat Med. 21: 914–921CrossRefPubMedPubMedCentral
17.
Morgan RA, Yang JC, Kitano M et al. (2010) Case report of a serious adverse event following the administration of T cells transduced with a chimeric antigen receptor recognizing ERBB2. Mol Ther. 18: 843–851CrossRefPubMedPubMedCentral
18.
Linette GP, Stadtmauer EA, Maus MV et al. (2013) Cardiovascular toxicity and titin cross-reactivity of affinity-enhanced T cells in myeloma and melanoma. Blood. 122: 863–871CrossRefPubMedPubMedCentral
19.
20.
Rosenberg SA, Restifo NP (2015) Adoptive cell transfer as personalized immunotherapy for human cancer. Science. 348: 62–68CrossRefPubMed
21.
Hartmann J, Schussler-Lenz M, Bondanza A, Buchholz CJ (2017) Clinical development of CAR T cells-challenges and opportunities in translating innovative treatment concepts. EMBO Mol Med 9:1183–1197CrossRefPubMedPubMedCentral
22.
Pearce KF, Hildebrandt M, Greinix H et al. (2014) Regulation of advanced therapy medicinal products in Europe and the role of academia. Cytotherapy 16: 289–297CrossRefPubMed
23.
24.
Robbins PF, Kassim SH, Tran TL et al (2014) A pilot trial using lymphocytes genetically engineered with an NY-ESO-1-reactive T cell receptor: long term follow up and correlates with response. Clin Cancer Res 21:1019–1027CrossRefPubMedPubMedCentral
25.
26.
Gattinoni L, Klebanoff CA, Palmer DC et al (2005) Acquisition of full effector function in vitro paradoxically impairs the in vivo antitumor efficacy of adoptively transferred CD8 + T cells. J Clin Invest 115:1616–1626CrossRefPubMedPubMedCentral
27.
Berger C, Jensen MC, Lansdorp PM et al (2008) Adoptive transfer of effector CD8 + T cells derived from central memory cells establishes persistent T cell memory in primates. J Clin Invest 118:294–305CrossRefPubMed
28.
29.
Riemke P, Czeh M, Fischer J et al. (2016) Myeloid leukemia with transdifferentiation plasticity developing from T-cell progenitors. EMBO J. 35: 2399–2416CrossRefPubMedPubMedCentral
30.
O’Reilly M, Shipp A, Rosenthal E et al. (2012) NIH oversight of human gene transfer research involving retroviral, lentiviral, and adeno-associated virus vectors and the role of the NIH recombinant DNA advisory committee. Methods Enzymol. 507: 313–335CrossRefPubMed
31.
Hacein-Bey-Abina S, Von Kalle C, Schmidt M et al (2003) LMO2-associated clonal T cell proliferation in two patients after gene therapy for SCID-X1. Science 302:415–419CrossRefPubMed
32.
Braun CJ, Boztug K, Paruzynski A et al (2014) Gene therapy for Wiskott–Aldrich syndrome–long-term efficacy and genotoxicity. Sci Transl Med 6:227ra33CrossRefPubMed
33.
34.
Riet T, Holzinger A, Dorrie J et al (2013) Nonviral RNA transfection to transiently modify T cells with chimeric antigen receptors for adoptive therapy. Methods Mol Biol 969:187–201CrossRefPubMed
35.
36.
37.
Monjezi R, Miskey C, Gogishvili T et al. (2016) Enhanced CAR T-cell engineering using non-viral Sleeping Beauty transposition from minicircle vectors. Leukemia. 31: 186–194CrossRefPubMed
38.
39.
Neelapu SS, Tummala S, Kebriaei P et al (2017) Chimeric antigen receptor T-cell therapy—assessment and management of toxicities. Nat Rev Clin Oncol 15:47–62CrossRefPubMed
40.
Ahmed N, Brawley VS, Hegde M et al (2015) Human epidermal growth factor receptor 2 (HER2) -specific chimeric antigen receptor-modified T cells for the immunotherapy of HER2-positive sarcoma. J Clin Oncol 33:1688–1696CrossRefPubMedPubMedCentral
41.
Davila ML, Riviere I, Wang X et al (2014) Efficacy and toxicity management of 19–28z CAR T cell therapy in B cell acute lymphoblastic leukemia. Sci Transl Med 6:224ra25CrossRefPubMedPubMedCentral
42.
Brentjens RJ, Davila ML, Riviere I et al (2013) CD19-targeted T cells rapidly induce molecular remissions in adults with chemotherapy-refractory acute lymphoblastic leukemia. Sci Transl Med 5:177ra38CrossRefPubMedPubMedCentral
43.
Suntharalingam G, Perry MR, Ward S et al (2006) Cytokine storm in a phase 1 trial of the anti-CD28 monoclonal antibody TGN1412. N Engl J Med 355:1018–1028CrossRefPubMed
44.
Bentley GA, Mariuzza RA (1996) The structure of the T cell antigen receptor. Annu Rev Immunol. 14: 563–590CrossRefPubMed
45.
46.
Aggen DH, Chervin AS, Schmitt TM et al. (2012) Single-chain ValphaVbeta T-cell receptors function without mispairing with endogenous TCR chains. Gene Ther. 19: 365–374CrossRefPubMed
47.
Cohen CJ, Li YF, El-Gamil M, Robbins PF, Rosenberg SA, Morgan RA (2007) Enhanced antitumor activity of T cells engineered to express T-cell receptors with a second disulfide bond. Cancer Res. 67: 3898–3903CrossRefPubMedPubMedCentral
48.
Provasi E, Genovese P, Lombardo A et al. (2012) Editing T cell specificity towards leukemia by zinc finger nucleases and lentiviral gene transfer. Nat Med. 18: 807–815CrossRefPubMedPubMedCentral
49.
Sommermeyer D, Uckert W (2010) Minimal amino acid exchange in human TCR constant regions fosters improved function of TCR gene-modified T cells. J Immunol 184:6223–6231CrossRefPubMed
50.
Knies D, Klobuch S, Xue SA et al (2016) An optimized single chain TCR scaffold relying on the assembly with the native CD3-complex prevents residual mispairing with endogenous TCRs in human T-cells. Oncotarget 7:21199–21221CrossRefPubMedPubMedCentral
51.
Matsui K, Boniface JJ, Steffner P et al (1994) Kinetics of T-cell receptor binding to peptide/I-Ek complexes: correlation of the dissociation rate with T-cell responsiveness. Proc Natl Acad Sci USA 91:12862–12866CrossRefPubMedPubMedCentral
52.
Gascoigne NR, Rybakin V et al. (2016) TCR signal strength and T cell development. Annu Rev Cell Dev Biol. 32: 327–348CrossRefPubMed
53.
Cherkassky L, Morello A, Villena-Vargas J et al (2016) Human CAR T cells with cell-intrinsic PD-1 checkpoint blockade resist tumor-mediated inhibition. J Clin Invest 126:3130–3144CrossRefPubMedPubMedCentral
54.
55.
56.
Singh H, Figliola MJ, Dawson MJ et al (2011) Reprogramming CD19-specific T cells with IL-21 signaling can improve adoptive immunotherapy of B-lineage malignancies. Cancer Res 71:3516–3527CrossRefPubMedPubMedCentral
57.
Ciceri F, Bonini C, Marktel S et al. (2007) Antitumor effects of HSV-TK-engineered donor lymphocytes after allogeneic stem-cell transplantation. Blood. 109: 4698–4707CrossRefPubMed
58.
Paszkiewicz PJ, Frassle SP, Srivastava S et al (2016) Targeted antibody-mediated depletion of murine CD19 CAR T cells permanently reverses B cell aplasia. J Clin Invest 126:4262–4272CrossRefPubMedPubMedCentral
59.
Cartellieri M, Bachmann M, Feldmann A et al. (2010) Chimeric antigen receptor-engineered T cells for immunotherapy of cancer. J Biomed Biotechnol. 2010: 956304CrossRefPubMedPubMedCentral
60.
Cartellieri M, Feldmann A, Koristka S et al (2016) Switching CAR T cells on and off: a novel modular platform for retargeting of T cells to AML blasts. Blood Cancer J 6:e458CrossRefPubMedPubMedCentral
61.
Albert S, Arndt C, Feldmann A et al (2017) A novel nanobody-based target module for retargeting of T lymphocytes to EGFR-expressing cancer cells via the modular UniCAR platform. Oncoimmunology 6:e1287246CrossRefPubMedPubMedCentral
62.
Feldmann A, Arndt C, Bergmann R et al (2017) Retargeting of T lymphocytes to PSCA- or PSMA positive prostate cancer cells using the novel modular chimeric antigen receptor platform technology “UniCAR”. Oncotarget 8:31368–31385PubMedPubMedCentral
63.
64.
Turtle CJ, Hanafi LA, Berger C et al (2016) CD19 CAR-T cells of defined CD4+:CD8 + composition in adult B cell ALL patients. J Clin Invest 126:2123–2138CrossRefPubMedPubMedCentral
65.
Maude SL, Barrett D, Teachey DT, Grupp SA (2014) Managing cytokine release syndrome associated with novel T cell-engaging therapies. Cancer J. 20: 119–122CrossRefPubMedPubMedCentral
66.
Brentjens R, Yeh R, Bernal Y et al (2010) Treatment of chronic lymphocytic leukemia with genetically targeted autologous T cells: case report of an unforeseen adverse event in a phase I clinical trial. Mol Ther 18:666–668CrossRefPubMedPubMedCentral
67.
Kochenderfer JN, Yu Z, Frasheri D et al (2010) Adoptive transfer of syngeneic T cells transduced with a chimeric antigen receptor that recognizes murine CD19 can eradicate lymphoma and normal B cells. Blood 116:3875–3886CrossRefPubMedPubMedCentral
68.
Bassani-Sternberg M, Braunlein E, Klar R et al (2016) Direct identification of clinically relevant neoepitopes presented on native human melanoma tissue by mass spectrometry. Nat Commun 7:13404CrossRefPubMedPubMedCentral
69.
Stronen E, Toebes M, Kelderman S et al (2016) Targeting of cancer neoantigens with donor-derived T cell receptor repertoires. Science 352:1337–1341CrossRefPubMed
70.
Verdegaal EM, de Miranda NF, Visser M et al. (2016) Neoantigen landscape dynamics during human melanoma-T cell interactions. Nature. 536: 91–95CrossRefPubMed
71.
72.
Schubert ML, Hückelhoven A, Hoffmann JM et al. (2016) Chimeric antigen receptor T cell therapy targeting CD19-positive leukemia and lymphoma in the context of stem cell transplantation. Hum Gene Ther. 27: 758–771CrossRefPubMed
73.
Schonfeld K, Sahm C, Zhang C et al (2015) Selective inhibition of tumor growth by clonal NK cells expressing an ErbB2/HER2-specific chimeric antigen receptor. Mol Ther 23:330–338CrossRefPubMed
74.
75.
Kalos M, June CH (2013) Adoptive T cell transfer for cancer immunotherapy in the era of synthetic biology. Immunity 39:49–60CrossRefPubMed
76.
77.
Davila ML, Brentjens R (2013) Chimeric antigen receptor therapy for chronic lymphocytic leukemia: what are the challenges? Hematol Oncol Clin North Am. 27: 341–353CrossRefPubMedPubMedCentral
78.
Lee DW, Kochenderfer JN, Stetler-Stevenson M et al. (2015) T cells expressing CD19 chimeric antigen receptors for acute lymphoblastic leukaemia in children and young adults: a phase 1 dose-escalation trial. Lancet. 385: 517–528CrossRefPubMed
79.
80.
Metadata
Title
Clinical translation and regulatory aspects of CAR/TCR-based adoptive cell therapies—the German Cancer Consortium approach
Publication date
01-04-2018
Published in
Cancer Immunology, Immunotherapy / Issue 4/2018
Print ISSN: 0340-7004
Electronic ISSN: 1432-0851
DOI
https://doi.org/10.1007/s00262-018-2119-y

Other articles of this Issue 4/2018

Cancer Immunology, Immunotherapy 4/2018 Go to the issue

Original Article

Reduction of myeloid-derived suppressor cells reinforces the anti-solid tumor effect of recipient leukocyte infusion in murine neuroblastoma-bearing allogeneic bone marrow chimeras

Original Article

Epstein–Barr virus strain heterogeneity impairs human T-cell immunity

Original Article

Abscopal effects of radiotherapy and combined mRNA-based immunotherapy in a syngeneic, OVA-expressing thymoma mouse model

Original Article

Cytosolic high-mobility group box protein 1 (HMGB1) and/or PD-1+ TILs in the tumor microenvironment may be contributing prognostic biomarkers for patients with locally advanced rectal cancer who have undergone neoadjuvant chemoradiotherapy

Original Article

Combined sublethal irradiation and agonist anti-CD40 enhance donor T cell accumulation and control of autochthonous murine pancreatic tumors

Original Article

Human c-SRC kinase (CSK) overexpression makes T cells dummy
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits