Mesane Kanserinde İmmunoloji ve İmmunoterapiler
Özet
Kanser immünoterapisinin temel amacı, bağışıklık sistemini güçlendirerek tümör hücrelerini ortadan kaldırmaktır. Tümörler anti-tümör bağışık yanıtını baskılamak için immün kontrol noktaları kullanırken, immün kontrol noktası blokajı (İKB) onkolojik tedavide önemli klinik faydalar sağlamaktadır. Mesane kanseri tedavisinde, yüksek mutasyon yükü ve PD-L1 ekspresyonu gibi biyolojik faktörler immünoterapiyi avantajlı kılmaktadır. Bu kapsamda FDA ve EMA tarafından onaylanmış atezolizumab, pembrolizumab, avelumab, durvalumab ve nivolumab gibi PD-1/PD-L1 inhibitörleri, T hücresi aktivasyonunu yeniden sağlayarak antitümoral etkinlik gösterir. Ayrıca, erken evre T hücresi aktivasyonunu düzenleyen CTLA-4'ün ipilimumab gibi antikorlarla bloke edilmesi de anti-tümör aktivitesini ortaya çıkarır. Sistemik immünoterapiler, platin bazlı kemoterapiye uygun olmayan veya tedavi sonrası ilerleme gösteren ileri evre mesane kanserli hastalarda birinci ve ikinci basamak tedavi seçeneği olarak sunulmaktadır. Geleceğe yönelik perspektiflerde ise EGFR ve HER-2 gen sinyal yollarına yönelik inhibitörler ile dendritik hücre bazlı aşılar gibi yeni nesil hedefe yönelik yaklaşımlar araştırılmaktadır. Mesane kanserinin genetik kararsızlığı ve hastanın bireysel özellikleri, doğru ve etkili tedavi stratejilerinin geliştirilmesinde anahtar rol oynamaktadır.
The primary goal of cancer immunotherapy is to eliminate tumor cells by strengthening the immune system. While tumors utilize immune checkpoints to suppress the anti-tumor immune response, immune checkpoint blockade (ICB) provides significant clinical benefits in oncological treatment. In the treatment of bladder cancer, biological factors such as a high mutational burden and PD-L1 expression render immunotherapy advantageous. Within this scope, PD-1/PD-L1 inhibitors approved by the FDA and EMA, including atezolizumab, pembrolizumab, avelumab, durvalumab, and nivolumab, demonstrate antitumoral efficacy by restoring T-cell activation. Additionally, blocking CTLA-4, which regulates early-stage T-cell activation, with antibodies like ipilimumab also unleashes anti-tumor activity. Systemic immunotherapies are offered as first- and second-line treatment options for patients with advanced bladder cancer who are ineligible for platinum-based chemotherapy or demonstrate progression after treatment. Regarding future perspectives, next-generation targeted approaches such as inhibitors directed at EGFR and HER-2 gene signaling pathways, as well as dendritic cell-based vaccines, are being investigated. The genetic instability of bladder cancer and the individual characteristics of the patient play a key role in developing accurate and effective treatment strategies.
Referanslar
Li, Y., Li, F., Jiang, F., Lv, X., Zhang, R., Lu, A., Zhang, G. (2016). A mini-review for cancer immunotherapy: Molecular understanding of PD-1/ PD-L1 pathway & translational blockade of immune checkpoints. International Journal of Molecular Sciences, 17(7), 1–22.
Rangel-Sosa, M. M., Aguilar-Córdova, E., Rojas-Martínez, A. (2017, September 30). Immunotherapy and gene therapy as novel treatments for cancer. Colombia Medica (Cali, Colombia).
Rowshanravan, B., Halliday, N., Sansom, D. M. (2018, January 4). CTLA-4: A moving target in immunotherapy. Blood. American Society of Hematology
Walker, L. S. K., Sansom, D. M. (2015, February 1). Confusing signals: Recent progress in CTLA-4 biology. Trends in Immunology. Elsevier Ltd
Gubin, M. M. ve ark., (2015). Checkpoint Blockade Cancer Immunotherapy Targets Tumour- Specific Mutant Antigens, Nature, vol. 515, no. 7528, 577–581.
Havel, J.J.; Chowell, D.; Chan, T.A. The evolving landscape of biomarkers for checkpoint inhibitor immunotherapy. Nat. Rev. Cancer. 2019, 19, 133‐150, doi: 10.1038/s41568‐019‐0116‐x.
Farina, M.S.; Lundgren, K.T.; Bellmunt, J. Immunotherapy in Urothelial Cancer: Recent Results and Future Perspectives. Drugs 2017, 77, 1077–1089, doi: 10.1007/s40265‐017‐0748‐7.
Rundo, F.; Spampinato, C.; Banna, G.L.; Conoci, S. Advanced Deep Learning Embedded Motion Radiomics Pipeline for Predicting Anti‐PD‐1/PD‐L1 İmmunotherapy Response in the Treatment of Bladder Cancer: Preliminary Results. Electronics 2019, 8, 1134, doi: 10.3390/electronics8101134
Alsaab, H.O.; Sau, S.; Alzhrani, R.; Tatiparti, K.; Bhise, K.; Kashaw, S.K.; Iyer, A.K. PD‐1 and PD‐L1 Checkpoint Signaling Inhibition for Cancer Immunotherapy: Mechanism, Combinations, and Clinical Outcome. Front. Pharmacol. 2017, 8, 561, doi: 10.3389/fphar.2017.00561.
Kim, T.J.; Cho, K.S.; Koo, K.C. Current Status and Future Perspectives of Immunotherapy for Locally Advanced or Metastatic Urothelial Carcinoma: A Comprehensive Review. Cancers 2020, 12, 192, doi: 10.3390/cancers12010192.
Chowdhury, F., Dunn, S., Mitchell, S., Mellows, T., AshtonKey, M., Gray, J. C. (2015). PD-L1 and CD8 + PD1 + lymphocytes exist as targets in the pediatric tumor microenvironment for immunomodulatory therapy. OncoImmunology, 4(10), e1029701.
Gibney, G. T., Weiner, P. L. M., Atkins, P. M. B., Comprehensive, L. (2016). Predictive biomarkers for checkpoint inhibitor-based immunotherapy. Lancet Oncol., 17(12), 542– 551.
Boussiotis, V. A. (2016). Molecular and Biochemical Aspects of the PD-1 Checkpoint Pathway. The New England Journal of Medicine, 375(18), 1767–1778.
Gibney, G. T., Weiner, P. L. M., Atkins, P. M. B., Comprehensive, L. (2016). Predictive biomarkers for checkpoint inhibitor-based immunotherapy. Lancet Oncol., 17(12), 542– 551.
Meng, Y., Liang, H., Hu, J., Liu, S., Hao, X., Wong, M. S. K., Hu, L. (2018). PD-L1 Expression Correlates With Tumor Infiltrating Lymphocytes And Response To Neoadjuvant Chemotherapy In Cervical Cancer. Journal of Cancer, 9(16), 2938–2945.
Wing, K., Yamaguchi, T., Sakaguchi, S., (2011). Cell-autonomous and -non-autonomous roles of CTLA-4 in immune regulation, Trends in Immunology, vol. 32, no. 9. 428–433.
Taube, J. M., Galon, J., Sholl, L. M., Rodig, S. J., Cottrell, T. R., Giraldo, N. A., David, L. (2018). Implications of the tumor immune microenvironment for staging and therapeutics. Mod Pathol., 31(2), 214–234.
Şimşek, M., Tekin, S. B., Bilici, M. (2019). Immunological Agents Used in Cancer Treatment. Eurasian J Med. 51(1): 90–94.
Donin NM, Lenis AT, Holden S, et al. Immunotherapy for the treatment of urothelial carcinoma. J Urol.2017;197(1):14-22.doi:10.1016/j. juro.2016.02.3005
Sharma P, Retz M, Siefker-Radtke A, et al. Nivolumab in metastatic urothelial carcinoma after platinum therapy (CheckMate275): a multicentre, single-arm, phase2 trial. Lancet Oncol.2017;18 (3):312-322.doi:10.1016/S1470-2045(17)30065-7
Powles T, O’Donnell PH, Massard C,et al. Efficacy and safety of durvalumab in locally advanced or metastatic urothelial carcinoma: updated results from a phase ½ open-label study. JAMA Oncol.2017;3(9):e172411.doi:10.1001/ jamaoncol.2017.2411
Apolo AB, Infante JR, Balmanoukian A, et al. Avelumab, an anti-programmed death-ligand 1 antibody, in patients with refractory metastatic urothelial carcinoma: results from a multicenter, phase Ib study. J Clin Oncol. 2017; 35 (19):2117-2124. doi:10.1200/JCO.2016.71.6795
12. Balar AV, Kamat AM, Kulkarni GS et al (2020) Pembrolizumab (pembro) for the treatment of patients with Bacillus CalmetteGuérin (BCG) unresponsive, high-risk (HR) non–muscle-invasive bladder cancer (NMIBC): Over two years follow-up of KEYNOTE-057. J Clin Oncol 38:5041–5041. https ://doi.org/10.1200/ jco.2020.38.15_suppl .5041
Y.M. Ning, D. Suzman, V.E. Maher, et al., FDA Approval Summary: atezolizumab for the Treatment of Patients with Progressive Advanced Urothelial Carcinoma after Platinum-Containing Chemotherapy, Oncologist 22 (6) (2017) 743–749.
J.E. Rosenberg, J. Hoffman-Censits, T. Powles, et al., Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: a single-arm, multicentre, phase 2 trial, Lancet 387 (10031) (2016) 1909–1920.
EAU Guidelines on Non‐muscle invasive Bladder Cancer (TaT1 and CIS) 2019. European Association of Urology. Available online: https://uroweb.org/wp‐content/uploads/05‐Non‐muscle‐Invasive BC_TaT1_201 9v2‐1.pdf (Accessed on 28 April 2020).
Farina, M.S.; Lundgren, K.T.; Bellmunt, J. Immunotherapy in Urothelial Cancer: Recent Results and Future Perspectives. Drugs 2017, 77, 1077–1089, doi: 10.1007/s40265‐017‐0748‐7.
FDA Approves Merck’s Keytruda (pembrolizumab) for Certain Patients with Locally Advanced or Metastatic Urothelial Carcinoma. Available online: https://www.drugs.com/newdrugs/fda‐approvesmerck‐s‐keytruda‐pembrolizumab‐certain‐patients‐locally‐advanced‐metastatic‐urothelial‐4536.html (accessed on 20 January 2020).
Morsch, R.; Rose, M.; Maurer, A.; Cassataro, M.A.; Braunschweig, T.; Knüchel, R.; Vögeli, T.A.; Ecke, T.; Eckstein, M.; Weyerer, V.; et al. Therapeutic implications of PD‐L1 expression in bladder cancer with squamous differentiation. BMC Cancer 2020, 20, doi:10.1186/s12885‐020‐06727‐2.
J. Bellmunt, R. de Wit, D.J. Vaughn, et al., Pembrolizumab as second-line therapy for advanced urothelial carcinoma, N Engl J Med 376 (11) (2017) 1015–1026.
D.J. Vaughn, J. Bellmunt, Y. Fradet, et al., Health-Related Quality-of-Life Analysis From KEYNOTE-045: a Phase III Study of Pembrolizumab Versus Chemotherapy for Previously Treated Advanced Urothelial Cancer, J Clin Oncol 36 (16) (2018) 1579–1587.
FDA Approves Bavencio (avelumab) for Metastatic Merkel Cell Carcinoma. Available online: https://www.drugs.com/newdrugs/fda‐approves‐bavencio‐avelumab‐metastatic‐merkel‐cell‐carcinoma4502.html (accessed on 10 December 2019).
Apolo, A.B.; Infante, J.R.; Balmanoukian, A.; Patel, M.R.; Wang, D.; Kelly, K.; Mega, A.E.; Britten, C.D.; Ravaud, A.; Mita, A.C.; et al. Avelumab, an Anti–Programmed Death‐Ligand 1 Antibody, In Patients With Refractory Metastatic Urothelial Carcinoma: Results From a Multicenter, Phase Ib Study. J. Clin. Oncol. 2017, 35, 2117–2124, doi: 10.1200/JCO.2016.71.6795
Rosenberg, J.E.; Hoffman‐Censits, J.; Powles, T.; van der Heijden, M.S.; Balar, A.V; Necchi, A.; Dawson, N.; O’Donnell, P.H.; Balmanoukian, A.; Loriot, Y.; et al. Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum‐based chemotherapy: a single‐arm, multicentre, phase 2 trial. Lancet 2016,387,1909–1920, doi: 10.1016/S01406736(16)00561‐4.
AstraZeneca’s Imfinzi (durvalumab) Receives FDA Accelerated Approval for Previously Treated Patients with Advanced Bladder Cancer Available online: https://www.drugs.com/newdrugs/astrazeneca‐simfinzi‐durvalumab‐receives‐fda‐accelerated‐approval‐previously‐treated‐patients‐4529.html (accessed on 20 January 2020).
PowlesT. O’Donnell P.H, Massard C, Arkenau H.‐T, Friedlander, T.W, Hoimes, C.J, Lee, J.L, Ong, M,Sridhar, S.S.,Vogelzang, N.J,et al. Efficacy and Safety of Durvalumab in Locally Advanced or Metastatic Urothelial Carcinoma. JAMA Oncol. 2017, 3, e172411, doi: 10.1001/jamaoncol.2017.2411.
Zajac, M.; Boothman, A.M.; Ben, Y.; Gupta, A.; Jin, X.; Mistry, A.; Sabalos, C.; Nielsen, A.; Manriquez, G.; Barker, C.; Antal, J.; Wang, P.; Patil, P.; Schechter, N.; Rebelatto, M.C.; Walker, J. Analytical Validation and Clinical Utility of an Immunohistochemical Programmed Death Ligand‐1 Diagnostic Assay and Combined Tumor and Immune Cell Scoring Algorithm for Durvalumab in Urothelial Carcinoma. Arch. Pathol. Lab. Med. 2018, 143, 722‐731, doi:10.5858/arpa.2017‐0555‐oa.
Bristol-Myers Squibb Receives FDA Approval for Opdivo (nivolumab) in Previously Treated Locally Advanced or Metastatic Urothelial Carcinoma. Available online: https://www.drugs.com/newdrugs/bristol‐myers‐squibb‐receives‐fda‐approval‐opdivo‐nivolumabpreviously‐treated‐locally‐advanced‐4484.html (accessed on 20 January 2020).
Sharma, P.; Callahan, M.K.; Bono, P.; Kim, J.; Spiliopoulou, P.; Calvo, E.; Pillai, R.N.; Ott, P.A.; de Braud, F.; Morse, M.; et al. Nivolumab monotherapy in recurrent metastatic urothelial carcinoma (CheckMate 032): a multicentre, open‐label, two‐stage, multi‐arm, phase 1/2 trial. Lancet Oncol. 2016, 17, 1590–1598, doi: 10.1016/S1470‐2045(16)30496‐X
Sharma, P.; Retz, M.; Siefker-Radtke, A.; Baron, A.; Necchi, A.; Bedke, J.; Plimack, E.R.; Vaena, D.; Grimm, M.‐O.; Bracarda, S.; et al. Nivolumab in metastatic urothelial carcinoma after platinum therapy (CheckMate 275): a multicentre, single-arm, phase 2 trial. Lancet Oncol. 2017,18,312-322, doi: 10.1016/S14702045 (17)30065‐7.
P. Sharma, M.K. Callahan, P. Bono, et al., Nivolumab monotherapy in recurrent metastatic urothelial carcinoma (CheckMate 032): a multicentre, open-label, two- stage, multi-arm, phase 1/2 trial, Lancet Oncol 17 (11) (2016) 1590–1598.
P. Sharma, A. Siefker-Radtke, F. de Braud, et al., Nivolumab Alone and With Ipilimumab in Previously Treated Metastatic Urothelial Carcinoma: checkMate 032 Nivolumab 1 mg/kg Plus Ipilimumab 3 mg/kg Expansion Cohort Results, J Clin Oncol 37 (19) (2019) 1608–1616.
Yervoy Approval History Available online: https://www.drugs.com/history/yervoy.html (accessed on 22 January 2020).
Carthon, B.C.; Wolchok, J.D.; Yuan, J.; Kamat, A.; Ng Tang, D.S.; Sun, J.; Ku, G.; Troncoso, P.; Logothetis, C.J.; Allison, J.P.; et al. Preoperative CTLA‐4 Blockade: Tolerability and Immune Monitoring in the Setting of a Presurgical Clinical Trial. Clin. Cancer Res. 2010, 16, 2861–2871, doi: 10.1158/1078‐0432.CCR‐10‐0569.
ElRazek, E.A.; Alhassanin, S.; Al Agizy, H.; Alhanafy, A.M.; Desoky, E.H. Immunotherapy for advanced bladder cancer: a new era. Menoufia Med. J. 2019, 32, 8–13, doi: 10.4103/mmj.mmj_768_17.
J.B. Aragon-Ching, A. Choudhury, V. Margulis, E.Y. Yu, Formidable scenarios in urothelial and variant cancers of the urinary tract, Am Soc Clin Oncol Educ Book 39 (2019) 262–275.
Jurkowska, K.; Długosz, A. Research on new drugs in the therapy of bladder cancer (BC). Postepy Hig. Med. Dosw. 2018, 72, 442–448, doi: 10.5604/01.3001.0012.0539.
Aragon-Ching, J.B.; Trump, D.L. Targeted therapies in the treatment of urothelial cancers. Urol. Oncol. Semin. Orig. Investig. 2017, 35, 465–472, doi: 10.1016/j.urolonc.2017.03.011.
Bladder Cancers Respond to EGFR Inhibitors. Cancer Discov. 2014, 4, 980.2‐981. 106.
Hussain, M.; Daignault, S.; Agarwal, N.; Grivas, P.D.; Siefker‐Radtke, A.O.; Puzanov, I.; MacVicar, G.R.; Levine, E.G.; Srinivas, S.; Twardowski, P.; et al. A randomized phase 2 trial of gemcitabine/cisplatin with or without cetuximab in patients with advanced urothelial carcinoma. Cancer 2014, 120, 2684–2693, doi: 10.1002/cncr.28767.
Iqbal, N.; Iqbal, N. Human Epidermal Growth Factor Receptor 2 (HER2) in Cancers: Overexpression and Therapeutic Implications. Mol. Biol. Int. 2014, 2014, doi: 10.1155/2014/852748. 108.
Peethambaram, P.P.; Melisko, M.E.; Rinn, K.J.; Alberts, S.R.; Provost, N.M.; Jones, L.A.; Sims, R.B.; Lin, L.R.C.; Frohlich, M.W.; Park, J.W. A phase I trial of immunotherapy with lapuleucel‐T (APC8024) in patients with refractory metastatic tumors that express HER‐2/neu. Clin. Cancer Res. 2009, 15, 5937–5944, doi: 10.1158/1078‐0432.CCR‐08‐3282.
Wołącewicz M, Hrynkiewicz R, Grywalska E, Suchojad T, Leksowski T, Roliński J, Niedźwiedzka-Rystwej P. Immunotherapy in Bladder Cancer: Current Methods and Future Perspectives. Cancers (Basel). 2020 May 7;12(5):1181. doi: 10.3390/cancers12051181. PMID: 32392774; PMCID: PMC7281703.
