Enhanced in vivo anti-tumor efficacy of whole tumor lysate in combination with whole tumor cell-specific polyclonal antibody

Ilnaz Rahimmanesh , Yasaman Esmaili, Elham Ghafouri, Seyed Hossein Hejazi, Hossein Khanahmad

Abstract


Background and purpose: Despite the widespread utilization of cancer vaccines with specified antigens, the use of whole tumor cell lysates in tumor immunotherapy would be a very promising approach that can overcome several significant obstacles in vaccine production. Whole tumor cells provide a broad source of tumor-associated antigens and can activate cytotoxic T lymphocytes and CD4+ T helper cells concurrently. On the other hand, as an effective immunotherapy strategy, recent investigations have shown that the multi-targeting of tumor cells with polyclonal antibodies, which are also more effective than monoclonal antibodies at mediating effector functions for target elimination, might minimize the escape variants.

Experimental approach: We prepared polyclonal antibodies by immunizing rabbits with the highly invasive 4T1 breast cancer cell line.

Findings/Results: In vitro investigation indicated that the immunized rabbit serum inhibited cell proliferation and induced apoptosis in target tumor cells. Moreover, in vivo analysis showed enhanced anti-tumor efficacy of whole tumor cell lysate in combination with tumor cell-immunized serum. This combination therapy proved beneficial in significant inhibition of the tumor growth and the established tumor was entirely eradicated in treated mice.

Conclusion and implications: Serial intravenous injections of tumor cell immunized rabbit serum significantly inhibited tumor cell proliferation and induced apoptosis in vitro and in vivo in combination with whole tumor lysate. This platform could be a promising method for developing clinical-grade vaccines and open up the possibility of addressing the effectiveness and safety of cancer vaccines.


Keywords


Breast cancer; Cancer vaccine; Immunotherapy; Polyclonal antibodies; Tumor cell lysate.

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References


Hu C, Hart SN, Gnanaolivu R, Huang H, Lee KY, Na J, et al. A population-based study of genes previously implicated in breast cancer. N Engl J Med. 2021;384(5):440-451. DOI: 10.1056/NEJMoa2005936.

Monkkonen T, Lewis MT. New paradigms for the Hedgehog signaling network in mammary gland development and breast Cancer. Biochim Biophys Acta Rev Cancer. 2017;1868(1):315-332. DOI: 10.1016/j.bbcan.2017.06.003.

Belli C, Trapani D, Viale G, D’Amico P, Duso BA, Vigna PD, et al. Targeting the microenvironment in solid tumors. Cancer Treat Rev. 2018;65:22-32. DOI: 10.1016/j.ctrv.2018.02.004.

Deepak KGK, Vempati R, Nagaraju GP, Dasari VR, Nagini S, Rao DN, et al. Tumor microenvironment: challenges and opportunities in targeting metastasis of triple negative breast cancer. Pharmacol Res. 2020;153:104683,1-35. DOI: 10.1016/j.phrs.2020.104683.

Bathula NV, Bommadevara H, Hayes JM. Nanobodies: the future of antibody-based immune therapeutics. Cancer Biother Radiopharm. 2021;36(2):109-122. DOI: 10.1089/cbr.2020.3941.

Rahimmanesh I, Khanahmad H. Chimeric antigen receptor-T cells immunotherapy for targeting breast cancer. Res Pharm Sci. 2021;16(5):447-454. DOI: 10.4103/1735-5362.323911.

Salewski I, Gladbach YS, Kuntoff S, Irmscher N, Hahn O, Junghanss C, et al. In vivo vaccination with cell line-derived whole tumor lysates: neoantigen quality, not quantity matters. J Transl Med. 2020;18(1):402,1-15. DOI: 10.1186/s12967-020-02570-y.

Rudnick JD, Sarmiento JM, Uy B, Nuno M, Wheeler CJ, Mazer MJ, et al. A phase I trial of surgical resection with Gliadel Wafer placement followed by vaccination with dendritic cells pulsed with tumor lysate for patients with malignant glioma. J Clin Neurosci. 2020;74:187-193.DOI: 10.1016/j.jocn.2020.03.006.

Gleisner MA, Pereda C, Tittarelli A, Navarrete M, Fuentes C, Ávalos I, et al. A heat-shocked melanoma cell lysate vaccine enhances tumor infiltration by prototypic effector T cells inhibiting tumor growth. J Immunother Cancer. 2020;8(2):1-12. DOI: 10.1136/jitc-2020-000999.

Yang H, Kuo Y, Smith ZI, Spangler J. Targeting cancer metastasis with antibody therapeutics. Wiley Interdiscip Rev Nanomedicine Nanobiotechnology. 2021;13(4):e1698,1-29. DOI: 10.1002/wnan.1698.

Barzaman K, Moradi-Kalbolandi S, Hosseinzadeh A, Kazemi MH, Khorramdelazad H, Safari E, et al. Breast cancer immunotherapy: current and novel approaches. Int Immunopharmacol. 2021;98:107886. DOI: 10.1016/j.intimp.2021.107886.

Goydel RS, Rader C. Antibody-based cancer therapy. Oncogene. 2021;40(21):3655-3664. DOI: 10.1038/s41388-021-01811-8.

Zahavi D, Weiner L. Monoclonal antibodies in cancer therapy. Antibodies (Basel). 2020;9(3):34,1-20. DOI: 10.3390/antib9030034.

Panahi Y, Mohammadzadeh AH, Behnam B, Orafai HM, Jamialahmadi T, Sahebkar A. A review of monoclonal antibody-based treatments in non-small cell lung cancer. Adv Exp Med Biol. 2021; 1286:49-64. DOI: 10.1007/978-3-030-55035-6_3.

Gupta A, Kumar Y. Bispecific antibodies: a novel approach for targeting prominent biomarkers. Hum Vaccin Immunother. 2020;16(11):2831-2839. DOI: 10.1080/21645515.2020.1738167.

Krishnamurthy A, Jimeno A. Bispecific antibodies for cancer therapy: a review. Pharmacol Ther. 2018;185:122-134. DOI: 10.1016/j.pharmthera.2017.12.002.

Ascoli CA, Aggeler B. Overlooked benefits of using polyclonal antibodies. Biotechniques. 2018;65(3):127-136.DOI: 10.2144/btn-2018-0065.

Dockray G. Validation of antibody-based assays for regulatory peptides: do it once, get it right, and exploit the under-appreciated benefit of long-term antibody stability. Peptides. 2019;114:8-9. DOI: 10.1016/j.peptides.2019.02.001.

Zhang S, Yu M, Deng H, Shen G, Wei Y. Polyclonal rabbit anti-human ovarian cancer globulins inhibit tumor growth through apoptosis involving the caspase signaling. Sci Rep. 2014;4(1):4984,1-7. DOI: 10.1038/srep04984.

Ahmadi-Noorbakhsh S, Mirabzadeh Ardakani E, Sadighi J, Aldavood SJ, Farajli Abbasi M, Farzad-Mohajeri S, et al. Guideline for the care and use of laboratory animals in Iran. Lab Anim (NY). 2021;50(11):1-3. DOI: 10.1038/s41684-021-00871-3.

Suárez NG, Báez GB, Rodríguez MC, Pérez AG, García LC, Fernández DRH, et al. Anti-proliferative and pro-apoptotic effects induced by simultaneous inactivation of HER1 and HER2 through endogenous polyclonal antibodies. Oncotarget. 2017;8(47):82872-82884. DOI: 10.18632/oncotarget.19958.

Li X, Huang F, Xu X, Hu S. Polyclonal rabbit anti-cancer-associated fibroblasts globulins induce cancer cells apoptosis and inhibit tumor growth. Int J Biol Sci. 2018;14(12):1621-1629. DOI: 10.7150/ijbs.26520.

Kumari S, Advani D, Sharma S, Ambasta RK, Kumar P. Combinatorial therapy in tumor microenvironment: where do we stand? Biochim Biophys Acta Rev Cancer. 2021;1876(2): 188585,1-39. DOI: 10.1016/j.bbcan.2021.188585.

Huang W, Chen JJ, Xing R, Zeng YC. Combination therapy: future directions of immunotherapy in small cell lung cancer. Transl Oncol. 2021;14(1): 100889,1-11. DOI: 10.1016/j.tranon.2020.100889.

Asadzadeh Z, Safarzadeh E, Safaei S, Baradaran A, Mohammadi A, Hajiasgharzadeh K, et al. Current approaches for combination therapy of cancer: the role of immunogenic cell death. Cancers (Basel). 2020;12(4):1047,1-38. DOI: 10.3390/cancers12041047.

Boone CE, Wang L, Gautam A, Newton IG, Steinmetz NF. Combining nanomedicine and immune checkpoint therapy for cancer immunotherapy. Wiley Interdiscip Rev Nanomedicine Nanobiotechnology. 2022;14(1): e1739,1-23. DOI: 10.1002/wnan.1739.

Ogino H, Taylor JW, Nejo T, Gibson D, Watchmaker PB, Okada K, Saijo A, et al. Randomized trial of neoadjuvant vaccination with tumor-cell lysate induces T cell response in low-grade gliomas. J Clin Invest. 2022,132(3):e151239,1-14.DOI: 10.1172/JCI151239.

Saxena M, van der Burg SH, Melief CJM, Bhardwaj N. Therapeutic cancer vaccines. Nat Rev Cancer. 2021;21(6):360-378.DOI: 10.1038/s41568-021-00346-0.

Sadeghi Najafabadi SA, Bolhassani A, Aghasadeghi MR. Tumor cell-based vaccine: an effective strategy for eradication of cancer cells. Immunotherapy. 2022;14(8):639-654. DOI: 10.2217/imt-2022-0036.

Lang F, Schrörs B, Löwer M, Türeci Ö, Sahin U. Identification of neoantigens for individualized therapeutic cancer vaccines. Nat Rev Drug Discov. 2022;21(4):261-282. DOI: 10.1038/s41573-021-00387-y.

Callmann CE, Cole LE, Kusmierz CD, Huang Z, Horiuchi D, Mirkin CA. Tumor cell lysate-loaded immunostimulatory spherical nucleic acids as therapeutics for triple-negative breast cancer. Proc Natl Acad Sci. 2020;117(30):17543-17550. DOI: 10.1073/pnas.2005794117.

Huber A, Dammeijer F, Aerts JGJV, Vroman H. Current state of dendritic cell-based immunotherapy: opportunities for in vitro antigen loading of different DC subsets? Front Immunol. 2018;9:2804,1-20.DOI: 10.3389/fimmu.2018.02804.

Laureano RS, Sprooten J, Vanmeerbeerk I, Borras DM, Govaerts J, Naulaerts S, et al. Trial watch: dendritic cell (DC)-based immunotherapy for cancer. Oncoimmunology. 2022;11(1):2096363,1-19. DOI: 10.1080/2162402X.2022.2096363.

Sondak VK, Sosman JA. Results of clinical trials with an allogeneic melanoma tumor cell lysate vaccine: Melacine®. Semin Cancer Biol. 2003;13(6):409-415. DOI: 10.1016/j.semcancer.2003.09.004.


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