Skip to main content

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

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.

This is a preview of subscription content, access via your institution.

Fig. 1

Abbreviations

ATMP:

Advanced therapy medicinal product

CARTOX:

CAR-T-Cell-associated toxicity

CREST:

chimeric antigen receptor (CAR)-T cell related encephalopathy syndrome

CRS:

cytokine release syndrome

DKFZ:

Deutsches Krebsforschungszentrum (German Cancer Research Center)

DKTK:

Deutsches Konsortium für Translationale Krebsforschung (German Cancer Consortium)

DLI:

donor lymphocyte infusion

DZG:

Deutsche Zentren der Gesundheitsforschung

EGFR:

epidermal growth factor receptor

ErbB2, HER2/neu:

human epidermal growth factor receptor 2

GMO:

genetically modified organism

GMP:

good manufacturing practice

GTMP:

gene therapy medicinal product

HZDR:

Helmholtz Zentrum Dresden Rossendorf

IMP:

investigational medicinal product

NCT:

Nationales Centrum für Tumorerkrankungen

PEI:

Paul-Ehrlich-Institut

TUM:

Technische Universität München

References

  1. Thomas ED (1975) Bone marrow transplantation: prospects for leukemia and other conditions. Proc Inst Med Chic 30:256–258

    CAS  PubMed  Google Scholar 

  2. Gyurkocza B, Rezvani A, Storb RF (2010) Allogeneic hematopoietic cell transplantation: the state of the art. Expert Rev Hematol. 3: 285–299

    Article  PubMed  PubMed Central  Google Scholar 

  3. Kolb HJ (2008) Graft-versus-leukemia effects of transplantation and donor lymphocytes. Blood 112:4371–4383

    CAS  Article  PubMed  Google Scholar 

  4. Billingham RE (1966) The biology of graft-versus-host reactions. Harvey Lect 62:21–78

    PubMed  Google Scholar 

  5. Ferrara JL, Levine JE, Reddy P, Holler E (2009) Graft-versus-host disease. Lancet 373:1550–1561

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  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 33:1889–1894

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  7. Busch DH, Frassle SP, Sommermeyer D et al (2016) Role of memory T cell subsets for adoptive immunotherapy. Semin Immunol 28:28–34

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  8. Couzin-Frankel J (2013) Breakthrough of the year 2013. Cancer Immunother Sci 342:1432–1433

    CAS  Google Scholar 

  9. Maus MV, Fraietta JA, Levine BL et al (2014) Adoptive immunotherapy for cancer or viruses. Annu Rev Immunol 32:189–225

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  10. Grupp SA, Kalos M, Barrett D et al (2013) Chimeric antigen receptor-modified T cells for acute lymphoid leukemia. N Engl J Med 368:1509–1518

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  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 127:2980–2990

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  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: 535–546

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  14. Morgan RA, Dudley ME, Wunderlich JR et al (2006) Cancer regression in patients after transfer of genetically engineered lymphocytes. Science 314:126–129

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  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: 917–924

    Article  PubMed  PubMed Central  Google Scholar 

  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: 914–921

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  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: 843–851

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  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: 863–871

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  19. European Medicines Agency (2015) Reflection paper on classification of advanced therapy medicinal products. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2015/06/WC500187744.pdf. Accessed 21 May 2015

  20. Rosenberg SA, Restifo NP (2015) Adoptive cell transfer as personalized immunotherapy for human cancer. Science. 348: 62–68

    CAS  Article  PubMed  Google Scholar 

  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 9:1183–1197

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  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: 289–297

    Article  PubMed  Google Scholar 

  23. Gschweng E, De Oliveira S, Kohn DB (2014) Hematopoietic stem cells for cancer immunotherapy. Immunol Rev. 257: 237–249

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  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 21:1019–1027

    Article  PubMed  PubMed Central  Google Scholar 

  25. Glienke W, Esser R, Priesner C et al (2015) Advantages and applications of CAR-expressing natural killer cells. Front Pharmacol 6:21. https://doi.org/10.3389/fphar.2015.00021.eCollection2015

    Article  PubMed  PubMed Central  Google Scholar 

  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 115:1616–1626

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  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 118:294–305

    CAS  Article  PubMed  Google Scholar 

  28. Gattinoni L, Restifo NP (2013) Moving T memory stem cells to the clinic. Blood 121:567–568

    CAS  Article  PubMed  Google Scholar 

  29. Riemke P, Czeh M, Fischer J et al. (2016) Myeloid leukemia with transdifferentiation plasticity developing from T-cell progenitors. EMBO J. 35: 2399–2416

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  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: 313–335

    Article  PubMed  Google Scholar 

  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 302:415–419

    CAS  Article  PubMed  Google Scholar 

  32. Braun CJ, Boztug K, Paruzynski A et al (2014) Gene therapy for Wiskott–Aldrich syndrome–long-term efficacy and genotoxicity. Sci Transl Med 6:227ra33

    Article  PubMed  Google Scholar 

  33. Heemskerk MH (2010) T-cell receptor gene transfer for the treatment of leukemia and other tumors. Haematologica. 95: 15–19

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  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 969:187–201

    CAS  Article  PubMed  Google Scholar 

  35. Maiti SN, Huls H, Singh H et al. (2013) Sleeping beauty system to redirect T-cell specificity for human applications. J Immunother. 36: 112–123

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  36. Kebriaei P, Singh H, Huls MH et al (2016) Phase I trials using sleeping beauty to generate CD19-specific CAR T cells. J Clin Invest 126:3363–3376

    Article  PubMed  PubMed Central  Google Scholar 

  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: 186–194

    Article  PubMed  Google Scholar 

  38. Eyquem J, Mansilla-Soto J, Giavridis T et al (2017) Targeting a CAR to the TRAC locus with CRISPR/Cas9 enhances tumour rejection. Nature 543:113–117

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  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 15:47–62

    Article  PubMed  Google Scholar 

  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 33:1688–1696

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  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 6:224ra25

    Article  PubMed  PubMed Central  Google Scholar 

  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 5:177ra38

    Article  PubMed  PubMed Central  Google Scholar 

  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 355:1018–1028

    CAS  Article  PubMed  Google Scholar 

  44. Bentley GA, Mariuzza RA (1996) The structure of the T cell antigen receptor. Annu Rev Immunol. 14: 563–590

    CAS  Article  PubMed  Google Scholar 

  45. Bendle GM, Linnemann C, Hooijkaas AI et al (2010) Lethal graft-versus-host disease in mouse models of T cell receptor gene therapy. Nat Med 16:565–570. https://doi.org/10.1038/nm.2128

    CAS  Article  PubMed  Google Scholar 

  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: 365–374

    CAS  Article  PubMed  Google Scholar 

  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: 3898–3903

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  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: 807–815

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  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 184:6223–6231

    CAS  Article  PubMed  Google Scholar 

  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 7:21199–21221

    Article  PubMed  PubMed Central  Google Scholar 

  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 91:12862–12866

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  52. Gascoigne NR, Rybakin V et al. (2016) TCR signal strength and T cell development. Annu Rev Cell Dev Biol. 32: 327–348

    CAS  Article  PubMed  Google Scholar 

  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 126:3130–3144

    Article  PubMed  PubMed Central  Google Scholar 

  54. Guedan S, Chen X, Madar A et al (2014) ICOS-based chimeric antigen receptors program bipolar TH17/TH1 cells. Blood 124:1070–1080

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  55. Zhou X, Di Stasi A, Brenner MK (2015) iCaspase 9 suicide gene system. Methods Mol Biol 1317:87–105

    Article  PubMed  PubMed Central  Google Scholar 

  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 71:3516–3527

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  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: 4698–4707

    CAS  Article  PubMed  Google Scholar 

  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 126:4262–4272

    Article  PubMed  PubMed Central  Google Scholar 

  59. Cartellieri M, Bachmann M, Feldmann A et al. (2010) Chimeric antigen receptor-engineered T cells for immunotherapy of cancer. J Biomed Biotechnol. 2010: 956304

    Article  PubMed  PubMed Central  Google Scholar 

  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:e458

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  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:e1287246

    Article  PubMed  PubMed Central  Google Scholar 

  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 8:31368–31385

    PubMed  PubMed Central  Google Scholar 

  63. European Medicines Agency (2008) Guideline on the non-clinical studies required before first clinical use of gene therapy medicinal products. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003942.pdf. Accessed 30 May 2008

  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 126:2123–2138

    Article  PubMed  PubMed Central  Google Scholar 

  65. Maude SL, Barrett D, Teachey DT, Grupp SA (2014) Managing cytokine release syndrome associated with novel T cell-engaging therapies. Cancer J. 20: 119–122

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  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 18:666–668

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  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 116:3875–3886

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  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 7:13404

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  69. Stronen E, Toebes M, Kelderman S et al (2016) Targeting of cancer neoantigens with donor-derived T cell receptor repertoires. Science 352:1337–1341

    CAS  Article  PubMed  Google Scholar 

  70. Verdegaal EM, de Miranda NF, Visser M et al. (2016) Neoantigen landscape dynamics during human melanoma-T cell interactions. Nature. 536: 91–95

    CAS  Article  PubMed  Google Scholar 

  71. Tran E, Robbins PF, Lu YC et al (2016) T-cell transfer therapy targeting mutant KRAS in cancer. N Engl J Med 375:2255–2262

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  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: 758–771

    CAS  Article  PubMed  Google Scholar 

  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 23:330–338

    Article  PubMed  Google Scholar 

  74. Zhang C, Burger MC, Jennewein L et al (2016) ErbB2/HER2-Specific NK Cells for Targeted Therapy of Glioblastoma. J Natl Cancer Inst 108. https://doi.org/10.1093/jnci/djv375

    Article  Google Scholar 

  75. Kalos M, June CH (2013) Adoptive T cell transfer for cancer immunotherapy in the era of synthetic biology. Immunity 39:49–60

    CAS  Article  PubMed  Google Scholar 

  76. European Medicines Agency (2016) Guideline on strategies to identify and mitigate risks for first-in-human and early clinical trials with investigational medicinal products. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2016/11/WC500216158.pdf. Accessed 10 November 2016

  77. Davila ML, Brentjens R (2013) Chimeric antigen receptor therapy for chronic lymphocytic leukemia: what are the challenges? Hematol Oncol Clin North Am. 27: 341–353

    Article  PubMed  PubMed Central  Google Scholar 

  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: 517–528

    CAS  Article  PubMed  Google Scholar 

  79. Lee DW, Gardner R, Porter DL et al. (2014) Current concepts in the diagnosis and management of cytokine release syndrome. Blood. 124: 188–195

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  80. Bonifant CL, Jackson HJ, Brentjens RJ, Curran KJ (2016) Toxicity and management in CAR T-cell therapy. Mol Ther Oncolytics 3:16011. https://doi.org/10.1038/mto.2016.11.eCollection2016

    CAS  Article  PubMed  PubMed Central  Google Scholar 

Download references

Funding

Support for this publication was provided by the DKTK.

Author information

Authors and Affiliations

Authors

Contributions

All authors participated in writing and editing of the manuscript.

Corresponding author

Correspondence to Angela M. Krackhardt.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Krackhardt, A.M., Anliker, B., Hildebrandt, M. et al. Clinical translation and regulatory aspects of CAR/TCR-based adoptive cell therapies—the German Cancer Consortium approach. Cancer Immunol Immunother 67, 513–523 (2018). https://doi.org/10.1007/s00262-018-2119-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00262-018-2119-y

Keywords

  • CAR/TCR-transgenic T cells
  • Cellular therapy
  • Regulatory aspects
  • Clinical translation