Linfocitos T con receptores antigénicos quiméricos en la inmunoterapia del cáncer: el amanecer de una nueva era?

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1 Linfocitos T con receptores antigénicos quiméricos en la inmunoterapia del cáncer: el amanecer de una nueva era? Dr. Miguel Lozano Molero Jefe de Sección de Hemoterapia Servicio de Hemoterapia y Hemostasia Hospital Clínico Universitario Barcelona

Miguel Lozano Molero Jefe de Sección de Hemoterapia Servicio

3 Immune System Innate Surface barriers Inflammation Complement system Cellular barriers Natural killer cells Adaptative B Lymphocytes T Lymphocytes Killer T cells Helper T cells

4 Adaptative Immunity

5 Humoral Immunity

6 Cellular Immunity

7 Antibody Immunity and Cancer Macrophage Cancer cell Helper T cell Natural killer cell Cytotoxic T cell

8 T Cell Receptor Signaling Lee DW, et al. Clin Cancer Res 2012; 18: 2780

9 Chimeric Antigen Receptor Structure α-taa mab α-taa mab scfv CD3ζ TCR complex Bretjens RJ, Retroviral vector

10 Chimeric Antigen Receptor Structure

13 T Cell for Cancer Immunotherapy Jacobson CA, Blood 2011; 118:

14 MNC Collection Spectra Amicus Optia

15 Process Lee DW, et al. Clin Cancer Res 2012; 18: 2780

16 Advantatges of CARs HLA-independent antigen recognition CARs active in both CD4+ and CD8+ T cells Target antigens include proteins, carbohydrates and glycolipids Significant quantities of tumor specific T cells are rapidly generated Minimal risk of generating undesired autoimmunity of GvHD Bretjens RJ,

Significant quantities of tumor specific T cells are rapidly generated Minimal

17 First Generation CARs Signaling Lee DW, et al. Clin Cancer Res 2012; 18: 2780

18 T-Cells require in-vivo stimulation Bretjens RJ, et al. Nat Med 2003;9:279-86

19 Evolution in CAR design

20 New Generations CARs Signaling Lee DW, et al. Clin Cancer Res 2012; 18: 2780

21 Antigens targeted by CARs Sadelain M, et al. Cancer Discov 2013;3: 388

22 Sadelain M, et al. Cancer Discov 2013;3: 388

23 Genentech, Inc. and Biogen Idec, 2006

24 Second generation CD19 CAR T-cells in vivo Kowolik CM, et al. Can Res 2006;66: 10995

26 CD19 CAR T cells Patients diagnosed of stage I CLL in 1996 In 2002 for disease progression received two cicles of rituximab plus fludarabine. In 2006, four cycles rituximab plus fludarabine In February 2009, three cycles of bendamustine. No response In Decembe 2009, MNC apheresis collection In July 2010, CD19 CART cell administration Porter DL, et al. NEJM 2011; 365: 725

27 CD19 CAR T cells Day -4: chemotherapy for depletion of lymphocytes (pentostatin and cyclophosphamide) Day 0: infusion of a total of 3 x10 8 T cells of which 5% were transduced (1.46 x 10 5 cells per kg) in three days (10% on day 1, 30% on day 2 and 60% on day 3) No toxic effects on infusions were noted Porter DL, et al. NEJM 2011; 365: 725

28 Preparatory Regimens Lee DW, et al. Clin Cancer Res 2012; 18: 2780

29 Response CD19 CAR T cells Porter DL, et al. NEJM 2011; 365: 725

30 Response CD19 CAR T cells Porter DL, et al. NEJM 2011; 365: 725

34 Maude SL, et al. NEJM 2014; 371:

35 Results

36 Recaída CD19 neg Grupp S. AABB Annual Meeting, Filadelfia, 24 Oct 2014.

37 CD22

38 Results

39 CAR-T cell infusion safety

40 Cytokine Release Syndrome A constellation of inflammatory symptoms resulting from cytokine elevations associated with tumor lysis syndrome Elevated IFNγ, IL-6, and TNFα levels, Increases in IL-2, granulocyte macrophage colony-stimulating factor (GM-CSF), IL-10, IL-8, IL-5, and fracktalkine. IL-6 plays a central role

41 Cytokine Release Syndrome In most patients, CRS symptoms are mild and flulike, with fevers and myalgias. Some patients experience a severe inflammatory syndrome, including vascular leak, hypotension, pulmonary edema, and coagulopathy, resulting in multiorgan system failure Cytokine elevations are measurable in most patients, but the degree of elevation may not correlate with severity of CRS or response to therapy. Some patients experience symptoms without marked cytokine elevation, whereas others demonstrate laboratory findings out of proportion to clinical symptoms

42 Signs and symptoms associated with CRS Lee DW, et al. Blood 2014; 124: 188

43 CRS revised grading system Lee DW, et al. Blood 2014; 124: 188

44 Treatment Lee DW, et al. Blood 2014; 124: 188

45 Anti IL-6: Tocilizumab

46 Conclusiones El tratamiento con linfocitos T modificados con receptores antigénicos quiméricos ofrece resultados muy prometedores en el tratamiento de neoplasias en base a los estudios pre-clínicos y clínicos Sin embargo persisten obstáculos significativos, tales como: Toxicidad Limitada persistencias in vivo de los linfocitos T modificados Limitada actividad anti-tumoral de los linfocitos T modificados en el hostil microambiente del tumor Recaída del tumor con células negativas para el antígeno reconocido por los linfocitos T modificados

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