Abstract
Most of the early monoclonal antibodies against target molecules on tumor cells for cancer therapy were naked antibodies without payloads. They can induce tumor cell death by the Fc-mediated effector functions of ADCC (antibody-dependent cellular cytotoxicity), ADCP (antibody-dependent cellular phagocytosis), and CDC (complement-dependent cytotoxicity) or by inhibiting the signaling pathway of growth hormone receptors on the tumor cell surface. The IgG1 subtype is usually chosen for eliminating tumor cells by ADCC and ADCP since it has a high affinity for the Fcγ receptors and is a potent activator of natural killer (NK) cells. Another approach has been to block the growth signals of angiogenesis (blood vessel formation) necessary for tumor nourishment. More recently, the use of antibodies directed against immune checkpoints on immune cells has made a major impact on the treatment of solid tumors. They have opened a window for treating cancers such as malignant melanomas that were previously resistant to therapy. Tumors that are particularly amenable to treatment with IC inhibitors are characterized by a high mutation rate and a significant number of tumor-infiltrating lymphocytes (TILs). However, not all patients with these so-called “hot” tumors respond due to the highly immunosuppressive tumor microenvironment. Recent advances in our understanding of these resistance mechanisms could provide new strategies for combining antibodies directed at ICs with other complementary therapeutic approaches.
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Selected Literature
Akalu YT, Rothlin CV, Ghosh S. TAM receptor tyrosine kinases as emerging targets of innate immune checkpoint blockade for cancer therapy. Immunol Rev. 2017;276(1):165–77. https://doi.org/10.1111/imr.12522.
Allegra CJ, Yothers G, O’Connell MJ, et al. Phase III trial assessing bevacizumab in stages II and III carcinoma of the colon: results of NSABP protocol C-08. J Clin Oncol. 2011;29:11–6. https://doi.org/10.1200/JCO.2010.30.0855.
Baselga J, Cortés J, Kim S-B. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med. 2012;366(2):109–19. https://doi.org/10.1056/NEJMoa1113216.
Bonaventura P, Shekarian T, Alcazer V, et al. Cold tumors: a therapeutic challenge for immunotherapy. Front Immunol. 2019;10:168. https://doi.org/10.3389/fimmu.2019.00168.
Bridgewater JA, Pugh SA, Maishman T. Systemic chemotherapy with or without cetuximab in patients with resectable colorectal liver metastasis (new EPOC): long-term results of a multicentre, randomised, controlled, phase 3 trial. Lancet Oncol. 2020;21:398–411. https://doi.org/10.1016/S1470-2045(19)30798-3.
Campesato LF, Weng C-H, Merghoub T. Innate immune checkpoints for cancer immunotherapy: expanding the scope of non T cell targets. Ann Transl Med. 2020;8(16):1031. https://doi.org/10.21037/atm-20-1816.
Chen J, Zhong M-C, Guo H. SLAMF7 is critical for phagocytosis of haematopoietic tumour cells via mac-1 integrin. Nature. 2017;544(7651):493–7. https://doi.org/10.1038/nature22076.
Chiu ML, Goulet DR, Teplyakov A, Gilliland GL. Antibody structure and function: the basis for engineering therapeutics. Antibodies. 2019;8(4):55. https://doi.org/10.3390/antib8040055.
Coiffier B, Thieblemont C, Van Den Neste E. Long-term outcome of patients in the LNH-98.5 trial, the first randomized study comparing rituximab-CHOP to standard CHOP chemotherapy in DLBCL patients: a study by the Groupe d’Etudes des Lymphomes de l’Adulte. Blood. 2010;116(12):2040–5. https://doi.org/10.1182/blood-2010-03-276246.
Cortés J, Baselga J, Im Y-H, et al. Health-related quality-of-life assessment in CLEOPATRA, a phase III study combining pertuzumab with trastuzumab and docetaxel in metastatic breast cancer. Ann Oncol. 2013;24:2630–5. https://doi.org/10.1093/annonc/mdt274.
Dahan R, Barnhart BC, Li F, et al. Therapeutic activity of agonistic, human anti-CD40 monoclonal antibodies requires selective FcγR engagement. Cancer Cell. 2016;29(6):820–31. https://doi.org/10.1016/j.ccell.2016.05.001.
Delves PJ, Martin SJ, Burton DR, Roitt IM, et al. Roitt’s essential immunology. 13th ed. Hoboken: Wiley; 2017.
Feng M, Jiang W, Kim BYS, et al. Phagocytosis checkpoints as new targets for cancer immunotherapy. Nat Rev Cancer. 2019;19(10):568–86. https://doi.org/10.1038/s41568-019-0183-z.
Galon J, Costes A, Sanchez-Cabo F. Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science. 2006;313:1960–4. https://doi.org/10.1126/science.1129139.
Horvath CJ, Milton MN. The TeGenero incident and the Duff report conclusions: a series of unfortunate events or an avoidable event? Toxicol Pathol. 2009;37(3):372–83. https://doi.org/10.1177/0192623309332986.
Hurwitz H, Fehrenbacher L, Novotny W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med. 2004;350:2335–42.
Karapetis CS, Khambata-Ford S, Jonker DJ. K-ras mutations and benefit from cetuximab in advanced colorectal cancer. N Engl J Med. 2008;359:1757–65.
Kaur S, Cicalese KV, Banerjee R, Roberts DD. Preclinical and clinical development of therapeutic antibodies targeting functions of CD47 in the tumor microenvironment. Antibody Ther. 2020;3(3):179–92. https://doi.org/10.1093/abt/tbaa017.
Kim N, Kim HS. Targeting checkpoint receptors and molecules for therapeutic modulation of natural killer cells. Front Immunol. 2018;9:2041. https://doi.org/10.3389/fimmu.2018.02041.
Kumar V, Patel S, Tcyganov E, Gabrilovich DI. The nature of myeloid-derived suppressor cells in the tumor microenvironment. Trends Immunol. 2016;37(3):208–20. https://doi.org/10.1016/j.it.2016.01.004.
Larkin J, Chiarion-Sileni V, Gonzalez R, et al. Five-year survival with combined nivolumab and ipilimumab in advanced melanoma. N Engl J Med. 2019;381:1535–46. https://doi.org/10.1056/NEJMoa1910836.
Leach DR, Krummel MF, Allison JP. Enhancement of antitumor immunity by CTLA-4 blockade. Science. 1996;271:1734–6.
Little M, editor. Recombinant antibodies for immunotherapy. 1st ed. Cambridge: Cambridge University Press; 2009.
Lu R-M, Hwang Y-C, Liu I-J, et al. Development of therapeutic antibodies for the treatment of diseases. J Biomed Sci. 2020;27:1. https://doi.org/10.1186/s12929-019-0592-z.
Malfitano AM, Pisanti S, Napolitano F, et al. Tumor-associated macrophage status in cancer treatment. Cancers. 2020;12(7):1987. https://doi.org/10.3390/cancers12071987.
Marin-Acevedo JA, Soyano AE, Dholaria B, et al. Cancer immunotherapy beyond immune checkpoint inhibitors. J Hematol Oncol. 2018;11(1):8. https://doi.org/10.1186/s13045-017-0552-6.
Mlcochova J, Faltejskova-Vychytilova P, Ferracin M, et al. MicroRNA expression profiling identifies miR-31-5p/3p as associated with time to progression in wild-type RAS metastatic colorectal cancer treated with cetuximab. Oncotarget. 2015;6(36):38695–704.
Moja L, Tagliabue L, Balduzzi S, et al. Trastuzumab containing regimens for early breast cancer. Cochrane Database Syst Rev. 2012;(4):CD006243. https://doi.org/10.1002/14651858.CD006243.pub2.
Murphy K, Weaver C. Janeway’s immunobiology. 9th ed. New York: WW Norton & Company; 2016.
Nishimura H, Nose M, Hiai H, Minato N, Honjo T, et al. Development of lupus-like autoimmune diseases by disruption of the PD-1 gene encoding an ITIM motif-carrying immunoreceptor. Immunity. 1999;11:141–51.
Pierpont TM, Limper CB, Richards KL. Past, present, and future of rituximab—the world’s first oncology monoclonal antibody therapy. Front Oncol. 2018;8:163. https://doi.org/10.3389/fonc.2018.00163.
Qin S, Jiang J, Lu Y, et al. Emerging role of tumor cell plasticity in modifying therapeutic response. Signal Transduct Target Ther. 2020;5(1):228. https://doi.org/10.1038/s41392-020-00313-5.
Renner C. 20 years of rituximab treatment: what have we learnt? Future Oncol. 2019;15(36):4119–21.
Schumacher TN, Schreiber RD. Neoantigens in cancer immunotherapy. Science. 2015;348(6230):69–74.
Seidel JA, Otsuka A, Kabashima K. Anti-PD-1 and anti-CTLA-4 therapies in cancer: mechanisms of action, efficacy, and limitations. Front Oncol. 2018;8:86. https://doi.org/10.3389/fonc.2018.00086.
Shi R, Chai Y, Duan X, et al. The identification of a CD47-blocking “hotspot” and design of a CD47/PD-L1 dual-specific antibody with limited hemagglutination. Signal Transduct Target Ther. 2020;5:16.
Slamon DJ, Leyland-Jones B, Shak S, et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med. 2001;344(11):783–92. https://doi.org/10.1056/NEJM200103153441101.
Su S, Zhao J, Xing Y, et al. Immune checkpoint inhibition overcomes ADCP induced immunosuppression by macrophages. Cell. 2018;175:442–57. https://doi.org/10.1016/j.cell.2018.09.007.
Suntharalingam G, Perry MR, Ward S, et al. Cytokine storm in a phase 1 trial of the anti-CD28 monoclonal antibody TGN1412. N Engl J Med. 2006;355:1018–28.
Sutamtewagul G, Link BK. Novel treatment approaches and future perspectives in follicular lymphoma. Ther Adv Hematol. 2019;10:1–20. https://doi.org/10.1177/2040620718820510.
Tabernero J, Cohn AL, Obermannova R, et al. RAISE: a randomized, double-blind, multicenter phase III study of irinotecan, folinic acid, and 5-fluorouracil (FOLFIRI) plus ramucirumab (RAM) or placebo (PBO) in patients (pts) with metastatic colorectal carcinoma (CRC) progressive during or following first-line combination therapy with bevacizumab (bev), oxaliplatin (ox), and a fluoropyrimidine (fp). J Clin Oncol. 2015;33(3):512. https://doi.org/10.1200/jco.2015.33.3_suppl.512.
Tabernero J, Takayuki Y, Cohn AL, et al. Ramucirumab versus placebo in combination with second-line FOLFIRI in patients with metastatic colorectal carcinoma that progressed during or after first-line therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine (RAISE): a randomised, double-blind, multicentre, phase 3 study. Lancet Oncol. 2015;16(5):499–508. https://doi.org/10.1016/S1470-2045(15)70127-0.
Tang J, Shalabi A, Hubbard-Lucey VM. Comprehensive analysis of the clinical immuno-oncology landscape. Ann Oncol. 2018;29:84–91. https://doi.org/10.1093/annonc/mdx755.
Xu W, Dong J, Zheng Y. Immune checkpoint protein VISTA regulates antitumor immunity by controlling myeloid cell–mediated inflammation and immunosuppression. Cancer Immunol Res. 2019;7:1497–510. https://doi.org/10.1158/2326-6066.CIR-18-0489.
Zahavi D, Weiner L. Monoclonal antibodies in cancer therapy. Antibodies. 2020;9:34. https://doi.org/10.3390/antib9030034.
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Little, M. (2021). Mediation of Tumor Cell Death by Naked Antibodies. In: Antibodies for Treating Cancer. Springer, Cham. https://doi.org/10.1007/978-3-030-72599-0_6
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DOI: https://doi.org/10.1007/978-3-030-72599-0_6
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