Immunomodulatory drugs of monoclonal antibodies are innovative immunotherapeutic agents in oncology with fundamentally new mechanism of action. Innovation of the approach is exactly in philosophy of the tumor immunotherapy, which includes not a direct destruction of tumor cells under the influence of the drug, which inevitably accompanied with a number of severe side effects, but an elimination of the key mechanism of tumor induced immunosuppression, with the help of which neoplasia back out of immune surveillance. Pembrolizumab, humanized monoclonal antibody IgG4 to PD-1 molecule, is the most perfect representative of this group of immunobiological antitumor agents. Through blocking of the co-inhibitory receptor PD-1 on the surface of the specific cytotoxic CD8+ T-lymphocytes, which infiltrating a tumor, it provides a resistance of the effector immunocompetent cells to the immunosuppressive effects of the malignant cells, which implemented through the PD-1:PD-L1 и PD-1:PD-L2 axis. The drug cancels tumor-induced selective cell immunodeficiency, providing to the immune system a possibility to realize an effective cytotoxic response against neoplasia. The results of clinical trials allow to recommend pembrolizumab in patients with inoperable or unresponsive to ipilimumab and BRAF inhibitor metastatic melanoma. There are encouragingly preliminary results of trials of pembrolizumab in small cell lung cancer. The success of innovative immunotherapy in oncology open up promising prospects of the effective, safe and, most importantly, physiologically based treatment of the malignant human neoplasms.
Ahmadzadeh M., Johnson L.A., Heemskerk B. et al. (2009) Tumor antigen-specific CD8 T cells infiltrating the tumor express high levels of PD-1 and are functionally impaired. Blood, 114(8): 1537–1544.
Berger R., Rotem-Yehudar R., Slama G. et al. (2008) Phase I safety and pharmacokinetic study of CT-011, a humanized antibody interacting with PD-1, in patients with advanced hematologic malignancies. Clin. Cancer Res., 14: 3044–3051.
Callahan M.K., Yang A., Tandon S. et al. (2011) Evaluation of serum IL-17 levels during ipilimumab therapy: correlation with colitis. J. Clin. Oncol., 29 (http://meetinglibrary.asco.org/content/79357-102 abstr. 2505).
Deeks E.D. (2014) Nivolumab: a review of its use in patients with malignant melanoma. Drugs, 74: 1233–1239.
Delyon J., Mateus C., Lefeuvre D. et al. (2013) Experience in daily practice with ipilimumab for the treatment of patients with metastatic melanoma: an early increase in lymphocyte and eosinophil counts is associated with improved survival. Ann. Oncol., 24: 1697–1703.
Fanoni D., Tavecchio S., Recalcati S. et al. (2011) New monoclonal antibodies against B-cell antigens: possible new strategies for diagnosis of primary cutaneous B-cell lymphomas. Immunol. Lett., 134(2): 157–160.
Faraone V., Arsena A., De Pasquale M.C. (1993) Purified human IgG administration, after chemotherapy, to patients with colorectal carcinoma. Minerva Gastroenterol. Dietol., 39(1): 37–39.
Fishman P., Bar-Yehuda S., Shoenfeld Y. (2002) IVIg to prevent tumor metastases. Int. J. Oncol., 21(4): 875–880.
Galluzzi L., Kroemer G., Eggermont A. (2014a) Novel immune checkpoint blocker approved for the treatment of advanced melanoma. Oncoimmunology, 3(11): e967147.
Galluzzi L., Vacchelli E., Bravo-San Pedro J.M. et al. (2014b) Classification of current anticancer immunotherapies. Oncotarget., 5(24): 12472–12508.
Garon E.B. Balmanoukian A., Hamid O. et al. (2014) MK-3475 monotherapy for previously treated non-small cell lung cancer: preliminary safety and clinical activity. Clin. Cancer. Res., 20 (absrract № A20).
Hamanishi J., Mandai M., Iwasaki M., Okazaki T. et al. (2007) Programmed cell death 1 ligand 1 and tumor-infiltrating CD8+ T lymphocytes are prognostic factors of human ovarian cancer. Proc. Natl. Acad. Sci USA, 104(9): 3360–3365.
Hamid O., Robert C., Daud A. et al. (2013) Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma. N. Engl. J. Med., 369(2): 134–144.
Henick B.S., Herbst R.S., Goldberg S.B. (2014) The PD-1 pathway as a therapeutic target to overcome immune escape mechanisms in cancer. Expert. Opin. Ther. Targets, 18(12): 1407–1420.
Herbst R.S., Gordon M.S., Fine G.D. et al. (2013) A study of MPDL3280A enengineered PD-L1 antibody in patients with locally advanced or metastatic tumors. ASCO Meeting Abstract, 31: 3000.
Joseph R.W., Elassaiss-Schaap J., Wolchok J.D. et al. (2014) Baseline tumor size as an independent prognostic factor for overall survival in patients with metastatic melanoma treated with the anti-PD-1 monoclonal antibody MK-3475. J. Clin. Oncol., 32 (http://meetinglibrary.asco.org/content/134724144).
Kyi C., Postow M.A. (2014) Checkpoint blocking antibodies in cancer immunotherapy. FEBS Lett., 588(2): 368–376.
Langer C., Gadgeel S.M., Borghaei H. et al. (2016) Carboplatin and pemetrexed with or without pembrolizumab for advanced, non-squamous non-small-cell lung cancer: a randomised, phase 2 cohort of the open-label KEYNOTE-021 study. Lancet Oncology, Oct. 9 [Epub. ahead of print].
Ludvigsson J.F., Neovius M., Ye W., Hammarström L. (2015) IgA deficiency and risk of cancer: a population-based matched cohort study. J. Clin. Immunol., 35(2): 182–188.
Luke J.J., Ott P.A. (2015) PD-1 pathway inhibitors: the next generation of immunotherapy for advanced melanoma. Oncotarget., 6(6): 3479–3492.
Momtaz P., Postow M.A. (2014) Immunologic checkpoints in cancer therapy: focus on the programmed death-1 (PD-1) receptor pathway. Pharmgenomics. Pers. Med., 7: 357–365.
Murie-Fernández M., Gurpide A., de la Cruz S., de Castro P. (2006) Total remission of thymus carcinoma after treatment with intravenous immunoglobulin. Clin. Transl. Oncol., 8(9): 697–699.
Nishimura H., Nose M., Hiai H. et al. (1999) Development of lupus-like autoimmune diseases by disruption of the PD-1 gene encoding an ITIM motif-carrying immunoreceptor. Immunity, 11(2): 141–151.
Nishimura H., Okazaki T., Tanaka Y. et al. (2001) Autoimmune dilated cardiomyopathy in PD-1 receptor-deficient mice. Science, 291(5502): 319–322.
Pardoll D.M. (2012) The blockade of immune checkpoints in cancer immunotherapy. Nat. Rev. Cancer, 12(4): 252–264.
Reck M., Rodrigez-Abreu D., Robinson A.G. et al. (2016) Pemrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N. Eng. J. Med., Oct. 8 [Epub. ahead of print].
Ribas A., Hamid O., Daud A. et al. (2016) Association of Pembrolizumab with tumor response among patients with advanced melanoma. JAMA, 315(15): 1600–1609.
Ribas A., Wolchok J.D., Robert C. et al. (2015) Updated clinical efficacy of the anti-PD-1 monoclonal antibody pembrolizumab (MK-3475) in 411 patients with melanoma. Eur. J. Cancer, 51 (Suppl. 2): e24.
Robert C., Ribas A., Wolchok J.D. et al. (2014) Anti-programmed-death-receptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced melanoma: a randomised dose-comparison cohort of a phase 1 trial. Lancet, 384(9948): 1109–1117.
Thompson R.H., Webster W.S., Cheville J.C. et al. (2005) B7–H1 glycoprotein blockade: a novel strategy to enhance immunotherapy in patients with renal cell carcinoma. Urology, 66(5 Suppl.): 10–14.
Wolchok J.D., Kluger H., Callahan M.K. et al. (2013) Nivolumab plus ipilimumab in advanced melanoma. N. Engl. J. Med., 369(2): 122–133.
YERVOY® (ipilimumab) (2011) YERVOY® (ipilimumab) prescribing information, 11 р. (http://packageinserts.bms.com/pi/pi_yervoy.pdf).
Zeng J., See A.P., Phallen J. et al. (2013) Anti-PD-1 blockade and stereotactic radiation produce long-term survival in mice with intracranial gliomas. Int. J. Radiat. Oncol. Biol. Phys., 86(2): 343–349.