Uma breve historia da terapia celular
Head, Division of Hematology Hospital A Beneficência Portuguesa São Paulo The Catalysts Tumor Immunology’s Return to Life
➢ Coley’s observation
➢ Spontaneous regression of certain tumors
➢ Hansen RM, Libnoch JA. Remission of chronic lymphocytic leukemia after smallpox vaccination. Arch Intern Med. 1978 Jul;138(7):1137-8.
➢ Monoclonal antibody technology in 1975
➢ Tumor responses with cytokines (IL-2, IFN)
➢ GVL and DLI effect
➢ Better understanding of the immune system and escape mechanisms New York Cancer Hospital General Memorial Hospital MSKCC
Ernest Codman James Ewing
William Coley 1925:Surgeon-in-Chief, Hospital of the Ruptured and Crippled NY,NY Hospital of Special Surgery (150 anos em 2015) Cornelius Rhoads James Douglas Realização:
1940
Paul Ehlich magischen kugeln,1890
“Imunização”
Realização: Late 1950’s – Proof of Principle
Realização:
Archives Cancer Research Institute
Timeline of Advances in Immunotherapy
Allogeneic BMT Donor Lymphocyte Infusions
Blinatumomab
Brentuximab Vedotin (Anti-CD30) Autologous Tumor Rituximab BMT Infiltrating (Anti-CD20) Lymphocytes CAR T Sipuleucel-T Therapies INF-α IL-2
1950 1960 1970 1980 1990 2000 2010 2015 Checkpoint Inhibitors Tumor Specificity Increases Over Time
12 Peptide vaccine CD40 DC vaccine Genetic vaccine CD137 IL-2 IFN OX40 CTLA4 IL-15 IL-21 PD1
Active immunotherapy Adoptive cell transfer (ACT) immunotherapy
TCR or CAR T cell cloning genetic engineering Types os imune-based therapies
• Antibody based • Naked antibody • Conjugated • Immune checkpoint • Cellular therapy • Cytokines • Vaccines • Adoptive cell transfer • BiTE
Adoptive cell immunotherapy
Team at Penn Medicine March 25 2015
April 4 2015 Adaptive Cell Transfer Therapy
Adoptive cell therapy (ACT) is a treatment that uses a cancer patient’s own T lymphocytes with anti-tumour activity, expanded in vitroand reinfused into the patient with cancer. Adaptive Cell Transfer Therapy
TIL (Tumor infiltration T-lymphocytes therapy)
TCR ( T-cell receptor therapy)
CAR-T (Chimeric antigen receptor T-cell therapy) Adoptive cell transfer immunotherapy
Rosenberg, S. A. (2014) Entering the mainstream of cancer treatment Nat. Rev. Clin. Oncol. doi:10.1038/nrclinonc.2014.174 Production of TIL for melanoma patients
leukapheresis
Digest and culture of tumor Day 0 rapid expansion TIL Day 6 - Day 14 Infusion and TIL T175 flask x 35 WAVE The first paper to demonstrate the regression of cancer using TIL for the immunotherapy of patients with metastatic melanoma.
Rosenberg, S. A.et al. Use of tumor infiltrating lymphocytes and interleukin-2 in the immunotherapy of patients with metastatic melanoma. Preliminary report. N. Engl. J. Med. 319, 1676–1680 (1988).
The T-cell receptor
TCR complex :TCR, CD3, ζ ITAM: immunoreceptor tyrosine-based activation motif system insystem other patients a melanomause them toengineerand Take the TCR genes from patientone whobeat melanoma lymphocyte Melanoma specific TCR Engineered AdoptiveCell Transfer - Melanoma TCR TCR
KVPRNQDWL HLA Melanoma Human lymphocyte redirected TCR - fighting immune fighting Melanoma TCR The first paper demonstrating the adoptive cell transfer of lymphocytes transduced with a retrovirus encoding TCRs that recognize a cancer antigen can mediate anti-tumour responses in patients with metastatic melanoma.
Morgan, R. A.et al.Cancer regression in patients after transfer of genetically engineered lymphocytes. Science 314, 126–129 (2006). ESO-3: Metastatic Synovial Sarcoma
6.18.2014 7.29.2014 1.9.2015
ACT with genetically modified lymphocytes TCR engineering
Recognizes MHC-peptide complexes Physiological T cell signaling CAR engineering
The history of CARs
The birth of CAR technology occurred 30 years ago when it was shown that antibody variable light (V L ) or heavy (V H ) gene segments can transfer specificity for native antigen.
It was Eshhar who realized the Translational potential of such non-HLA- restricted T cell recognition.
PNAS 86: 10024, 1989 Centro Oncológico BP
Beneficência Portuguesa Hospital BP Mirante