1、 Advances of dendritic-cell vaccine in clinical cancer therapy123ContentsDefinition & condition Clinical efficiencyTrends and new advances 4Conclusion Definition & condition 1What is dendrtic-cell vaccine Current condition What is dendritic cell abc1Dendritic cell (DC)centre of immune systemnatures

2、adjuvantsDiscovered by Cohn and Steinman in 19731 Palucka K, Banchereau J. Cancer immunotherapy via dendritic cells. Nat Rev Cancer. 2013,12(4): 265277.capture and process antigensmigrate to lymph nodespresent the antigen induce immune responsesDendritic-cell vaccine 3 Janikashvili N, Larmonier N, K

3、atsanis E. Personalized dendritic cell-based tumor immunotherapy. Immunotherapy. 2010,2(1): 57-68.Ex vivo preparation of dendritic cell-based anticancer vaccinesCurrent condition 2 Anguille S, Smits EL, Lion E, et al. Clinical use of dendritic cells for cancer therapy. Lancet Oncol 2014,15: 25767. C

4、linical efficiency2Safety aOverall objective responsebSurvival benefitsc2Safety Local reactionspainrashpruritusSystemic side-effectspyrexia 發熱malaise 萎靡influenza-like symptomscommonmild and self-limitingcan occursystemic grade 3-4 toxicity is extremely rare Feasible in many malignancies Well tolerat

5、ed with minimal toxicity Induce tumour-specific immune responses12 Radford KJ, Tullett KM, Lahoud MH. Dendritic cells and cancer immunotherapy. Current Opinion in Immunology 2014, 27:2632BADSAFEPhase 1 clinical studiesObjective responses to DC vaccination in different cancersCancerN=CRPRORmelanoma12

6、05/139436678.5% prostate cancer803/8945527.1%primary brain tumors (glioma)173/55032415.6%renal cell cancer287/34472611.5%*N=number of vaccinated patients evaluable for tumour response assessment/total number of patients. CR=complete response as defined by RECIST. PR=partial response as defined by RE

7、CIST. OR=proportion of patients achieving an objec tive response, calculated by dividing the sum of CR and PR by the number of vaccinated patients evaluable for tumour response assessment.2 Anguille S, Smits EL, Lion E, et al. Clinical use of dendritic cells for cancer therapy. Lancet Oncol 2014,15:

8、 25767.Overall objective response Benefit is real but small!Survival benefits An increase in median overall survival of at least 20%Overview of all published trials of DC vaccines in melanoma, prostate cancer, malignant glioma, and renal cell carcinomaMost convincing evidence：IMPACT study, phase 3 r

9、andomised controlled trialMetastatic hormone-resistant prostate cancerSipuleucel-T the DC-based therapeutic vaccineMedian overall survival: 25.8 months 21.7 months 2 Anguille S, Smits EL, Lion E, et al. Clinical use of dendritic cells for cancer therapy. Lancet Oncol 2014,15: 25767.8 Kantoff PW, Hig

10、ano CS, Shore ND, et al, and the IMPACT Study Investigators. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med 2010, 363: 41122.Sipuleucel-T was approved by the US Food and Drug Administration in 2010！1st Trends and new advances 3Next-generation DC vaccines aCombinati

11、on therapy bImprove activity of immunostimulatory Potentiate the effectiveness of DC immunotherapy3Conventional DC vaccines safelong-lasting survival benefits4 Sabado RL, Bhardwaj N. Cancer immunotherapy: Dendritic-cell vaccines on the move. Nature. 2015, 519: 300301.Limiting factors source and type

12、 of DCs usedsite and frequency of injectionability of DCs to migratepossibility of act indirectlynot so effectiveNext-generation DC vaccinesMaturation stimuli a combination of TNF-, IL- 1, interferon , interferon , and polyI:CExample:IL-12p70 & CXCL10 Th1 immune response T lymphocytes and NK cellsNe

13、xt-generation DC vaccines Cancer type malignant glioma13 Okada H, Kalinski P, Ueda R, et al. Induction of CD8+ T-cell responses against novel glioma-associated antigen peptides and clinical activity by vaccinations with alpha-type 1 polarized dendritic cells and polyinosinic-polycytidylic acid stabi

14、lized by lysine and carboxymethylcellulose in patients with recurrent malignant glioma. J Clin Oncol 2011; 29: 33036.1) Subtype desired capacityspecific immune responsematuration-inducing regimenpre-conditioninglocal inflammatory responsesDC migration ? tetanus/diphtheria破傷風/白喉 (Td) toxoid vaccineNe

15、xt-generation DC vaccines2) Pre-conditioningsimply improving DC migrationdramaticallly enhancing antitumour responses5 Mitchell DA, Batich KA, Gunn MD, et al. Tetanus toxoid and CCL3 improve dendritic cell vaccines in mice and glioblastoma patients. Nature. 2015, 519: 366-369.Figure : Optimizing den

16、dritic-cell vaccines4 Sabado RL, Bhardwaj N. Cancer immunotherapy: Dendritic-cell vaccines on the move. Nature. 2015, 519: 300301.Next-generation DC vaccines2 Anguille S, Smits EL, Lion E, et al. Clinical use of dendritic cells for cancer therapy. Lancet Oncol 2014,15: 25767.Combination therapy1. En

17、hance immune effector response cytotoxic T lymphocyte (CTL) natural killer cellCTLA-4PD-11) Immune checkpoint receptors negative regulation Combination therapy(ipilimumab)Anti-CTLA-4 monoclonal antibodyAnti-PD-1 monoclonal antibodyMonoclonal antibody preliminary clinical evidences(pidilizumab)14 Ham

18、id O, Robert C, Daud A, et al. Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma. N Engl J Med 2013, 369: 13444.15 Wolchok JD, Kluger H, Callahan MK, et al. Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med 2013; 369: 12233.1. Enhance immune effector response 9 Kirkwoo

19、d JM, Butterfield LH, Tarhini AA, et al. Immunotherapy of cancer in 2012. CA Cancer J Clin 2012,62: 30935.2) cytokines & Toll-like receptor agonists positive regulation Combination therapycytotoxic T lymphocyte (CTL) natural killer cellbe incorporated into the vaccine itselfapplied with DC vaccine a

20、t the same time2. Reverse tumour-associated immunosuppressionNegative immune regulatorsTregs DCs target Tregs themselves DCs combined with Treg-targeting drug MDSCs combine DC vaccine with MDSC-targeted interventionsVEGF inhibitorsCOX-2 inhibitors.10Jacobs JF, Nierkens S, Figdor CG, et al. Regulator

21、y T cells in melanoma: the final hurdle towards effective immunotherapy. Lancet Oncol 2012, 13: e3242.eg. FoxP3Combination therapyeg. basiliximab3. Reduce the tumour burden & increase the immune susceptibility of the tumour cells11Widn K, Mozaff ari F, Choudhury A, et al. Overcoming immunosuppressiv

22、e mechanisms. Ann Oncol 2008, 19: vii 24147.cytoreductive cancer treatments eg. chemotherapyconventional anticancer treatments eg. radiation therapy hormonal therapyCombination therapy Conclusion 34DC vaccinesatetyoverall immune reponsessurvival benefitsnot so effectiveImprovementsnext-generation DC

23、 vaccinecombination therapy subtypepre-conditioningimmune effector responseimmunosuppressiontumour burdenimmune susceptibilityHold the key to the full therapeutic potential of dendritic cells for cancer immunotherapy!References:1 Palucka K, Banchereau J. Cancer immunotherapy via dendritic cells. Nat

24、 Rev Cancer. 2013,12(4): 265277.2 Anguille S, Smits EL, Lion E, et al. Clinical use of dendritic cells for cancer therapy. Lancet Oncol. 2014,15: 25767.3 Janikashvili N, Larmonier N, Katsanis E. Personalized dendritic cell-based tumor immunotherapy. Immunotherapy. 2010,2(1): 57-68.4 Sabado RL, Bhard

25、waj N. Cancer immunotherapy: Dendritic-cell vaccines on the move. Nature. 2015, 519: 300301.5 Mitchell DA, Batich KA, Gunn MD, et al. Tetanus toxoid and CCL3 improve dendritic cell vaccines in mice and glioblastoma patients. Nature. 2015, 519: 366-369.6 Merad M, Salmon H. A dendritic-cell brake on a

26、ntitumour immunity. Nature. 2015, 523: 294-295.References:7 Palucka K, Banchereau J. Dendritic-cell-based therapeutic cancer vaccines. Immunity. 2013, 39(1):38-48.8 Kantoff PW, Higano CS, Shore ND, et al. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med. 2010, 363(5):411-22.9 Kirkwood JM, Butterfi eld LH, Tarhini AA, et al. Immunotherapy of cancer in 2012. CA Cancer J Clin 2012,62: 30935.10 Jacobs JF, Nierkens S, Figdor CG, et al. Regulatory T cells in melanoma: the final hurdle towards effective immunotherapy. Lancet Oncol 2012, 13: e3