Biotecnologia no combate ao câncer
Propaganda
Biotecnologia no combate ao câncer Martin Bonamino I SBERJ – 09-2013 Microambiente tumoral Biotecnologia como abordagem para combate ao câncer • Bloqueio de fatores estimuladores • Anticorpos Monoclonais específicos para o tumor • Anticorpos Monoclonais imuno-moduladores • Terapia celular/gênica Scott et al, Nat Rev Cancer 2012 mAbs: estruturas e alternativas Weidle et al, Cancer Gen Proteom 2013 Anticorpos Monoclonais: tumor como alvo Rituximab – mAb quimérico anti CD20 - IgG Rituximab – mAb quimérico anti CD20 - IgG Cetuximab – mAb quimérico anti EGFR – IgG1 Panitumumab – mAb humanizado anti EGFR – IgG2 Scott et al, Nat Rev Cancer 2012 Scott et al, Nat Rev Cancer 2012 Anticorpos Monoclonais: sistema imune como alvo Bloqueio de CTLA-4 Adapted from ASCO 2008 meeting. Suzanne Louise Topalian, MD T Cell Activation by TCR and Co-stimulation Through CD28 MHCAntigen TCR Dendritic cell T cell B7 CD28 CTLA4 CTLA4 Receptors Are Up-Regulated Following T-Cell Activation MHCAntigen TCR Dendritic cell T cell B7 CD28 CTLA4 CTLA4 Negatively Modulates T-Cell Activation MHCAntigen TCR Dendritic cell T cell CD28 B7 CTLA4 Blocking Antibodies to CTLA4 Allow Positive Signaling from Costimulatory Molecules to T Cells MHCAntigen TCR Dendritic cell T cell B7 CD28 CTLA4 Leach DR, Krummel MF, Allison JP. Enhancement of antitumor immunity by CTLA-4 blockade. Science 1996;271:1734-1736. Ipilimumab Improves Overall Survival compared to control Ipi + gp100 (A) Ipi alone (B) gp100 alone (C) 1 2 Years 3 4 Survival Rate Ipi + gp100 N=403 Ipi + pbo N=137 gp100 + pbo N=136 1 year 44% 46% 25% 2 year 22% 24% 14% What mediates anti-CTLA4-induced durable tumor regressions? 2005 Durable response > 5 years Blue: melanoma Brown: CD8+ T cells Treatment with anti-CTLA4 antibodies The great majority of responses last years without relapses: - Longest responder: Ongoing since May 2001 - Response rate: ~10% Metastatic Melanoma Response to Ipilimumab Before Ipilimumab 04/22/11 After Ipilimumab 08/05/11 Immunotherapy vs targeted therapy for melanoma Targeted therapy Percent alive Percent alive Immunotherapy 0 1 Years 2 3 0 1 Years 2 3 Bloqueio de PD1 Células tumorais são capazes de matar linfócitos efetores infiltrantes http://www.bmsimmunooncology.com/tumor-immunosuppression.aspx Expressão de PD-1L por células tumorais Marcação periférica Marcação difusa HPV-Associated Head and Neck Squamous Cell Carcinoma Lyford-Pike et al. CanRes 2013 Enhancing Immune Responsiveness PD1 Ab (MDX1106) Phase I, single dose, Tolerable, responses in Colon, Lung, MM, RCC Brahmer, ASCO 2008 PDL1 Ab Phase I trial ongoing PD1 Ab Phase 1, multi dose, tolerable, PRs in RCC, MM and Lung, Sznol, ASCO 2010 Durable partial regression of metastatic kidney cancer following 3 doses of anti-PD-1 (10 mg/kg) 01/15/08, pre-Rx 04/22/08 07/22/08 72 year old male with RCC metastatic to lung, LN, muscle, bone, pancreas. Prior therapies included HDAC inhibitor, sunitinib, and sorafenib. Brahmer et al., JCO 2010 Percent Change in Tumor Burden in RCC Patients *Patients treated with the 10 mg/kg dose †Upper horizontal line denotes no change; lower horizontal line denotes 30% decrease (RECIST threshold for PR). Abbreviations: PR = partial response; RCC = renal cell carcinoma; RECIST = Response Evaluation Criteria in Solid Tumors 33 Outros alvos de intervenção Kwek et al, Nat Rev Cancer 2012 Anticorpos Bi-específicos Frankel and Baeuerle, Curr Opin Chem Biol 2013 Peptide vaccine DC vaccine Genetic vaccine IL-2 IFN IL-15 IL-21 CTLA4 PD1 CD40 CD137 OX40 T cell cloning TCR or CAR genetic engineerin Terapia celular Tumor Infiltrating Lymphocytes 39 Immunotherapy Rosenberg and Dudley, Curr Opin Immunol 2009 Rosenberg and Dudley, Curr Opin Immunol 2009 ACT: Transferência adotiva de células NMA: Não Mieloablativo Terapia gênica Transferência gênica de TCR Receptores Quiméricos de Antígenos (CARs) Redirecting lymphocyte specificity for tumor elimination Chimeric Antigen Receptor (CAR) MHC-independent antigen recognition; High affinity for the antigen; Independent of patient- derived TILs Adapted from Pule et al, 2003 T lymphocyte activation Multiple signals required Chimeric Antigen Receptor (CAR) Acuto et al., 2003 Chimeric Antigen Receptor (CAR) 1st generation 2nd generation 3rd generation Clinical trials – 1st generation CAR Nature Medicine, 2008 Sadelain et al, Cancer Disc 2013 Clinical trials - 2nd generation CAR NHL – B cells CAR 19-28z Kochenderfer et al, Blood 2010 Clinical trials - 2nd generation CAR CLL-B CAR 19-BBz 10e7 cels Kalos M, et al. Sci Transl Med 2011 Porter DL, et al. N Engl J Med 2011 Grupp, et al. N Engl J Med 2013 Sleeping Beauty Transposon Chicaybam et al, 2013 Sleeping Beauty Transposon Chicaybam et al, 2013 Strategies to circumvent adverse effects a) c) b) d) Chicaybam et al, 2011 Challenges and Solutions in Cancer Research and Treatment Club Med Mangaratiba, Rio de Janeiro, Brazil April 27-30, 2014 [email protected]