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scFv6.C4 DNA vaccine with fragment C of tetanus toxin increases protective immunity against CEA-expressing tumor

Gene Therapy volume 28, pages 287–289 (2021)Cite this article

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Zanetti et al. have recently published a paper highlighting scFv6.C4 DNA vaccine with fragment C of tetanus toxin as a potential preventive therapeutic against carcinoembryonic antigen (CEA)-expressing colorectal cancers [1]. Despite advances in surgical and treatment modalities, colorectal cancer remains as the third leading cause of cancer-related mortality in men and in women in the United States alone [2,3,4]. Carcinoembryonic antigen (CEA) is one of the major tumor-associated antigens (TAA) in colorectal cancers. This protein is more often highly expressed in fetal developmental stages, and either not expressed or expressed in trace amounts in adult colon epithelium, hence considering it as self-antigen. Considering the fact that this self-antigen in colorectal cancer can activate the immune system by suppression of cell-mediated immunity (Th1 CD4+ T lymphocytes), and cause a shift toward humoral-mediated immunity (Th2 CD4+ lymphocytes) [5], Zanetti et al. utilized this mechanism for developing a DNA vaccine against CEA-expressing colorectal tumors using a murine anti-idiotypic CEA surrogate—scFv6.C4 that can mimic CEA functionality, yet behave as a xenoantigen or non-self-antigen that can circumvent immune tolerance, and evoke potent anti-CEA humoral and cell-mediated responses [6]. To increase its efficiency at the clinical level, Zanetti and group fused this anti-idiotypic CEA surrogate with a commonly used adjuvant fragment C (FrC) of tetanus toxin, found to trigger CD4+ and CD8+ proliferative response, and strong CD8+ cytotoxic T-cell lymphocyte (CTL) responses and Th1 helper immune responses, thus effectively delaying tumor growth in CEA2682 transgenic mice previously challenged with MC38-CEA tumor cells [1]. It is noteworthy to discuss here that Zanetti et al. have referred several similar kinds of DNA vaccines in which FrC fused to side-chain variable fragment (scFv) region of anti-idiotype monoclonal antibodies has been developed against various cancer-specific antigens in several preclinical trials against lymphomas and melanomas to develop humoral and cellular responses and delay tumor growth [7], and Phase-I and -II clinical trials in myeloma and prostatic cancer showed safety and tolerance against the vaccines, inducing antigen-specific CD8+ T-cell responses [8]. From the past one decade, several other groups have made efforts to develop CEA anti-idiotype monoclonal antibody vaccines that show potential to break immune tolerance to CEA and induce high-titer anti-CEA antibody as well as CEA-specific CD4+ T-helper responses in colon cancer patients (Phase I/II clinical trials) and in human CEA transgenic mice [9,10,11]. For instance, Chatterjee et al. have published few similar papers wherein they developed an anti-idiotype Ab2, CEA antibody (CeaVac) generated in BALB/c mice against a specific CEA epitope that has no cross-reactivity with nonspecific cross-reacting antigen and biliary glycoprotein, and vaccinated in Dukes’ B, C, and D colon cancer patients immediately after surgical resection, as well as in human CEA transgenic mice, in an attempt to determine immune response of chemotherapy with a 5-fluorouracil (5-FU) regimen administered with CeaVac. This group demonstrated that 100% of 32 patients treated on a Phase II clinical trial had the ability to break immune tolerance to CEA using the combinatorial approach. However, this combination treatment only improved the overall patient immune responses as compared with standard treatments as long as the patients received CeaVAC monthly injections [12]. Another group led by Cunningham conducted a randomized Phase III clinical trial to determine the clinical efficacy of 5-FU/leucovorin (LV) plus an anti-idiotype monoclonal antibody 3H1 in previously untreated advanced metastatic colorectal cancer patients. They observed a strong anti-CEA antibody response and less toxicity in 5-FU/LV when combined with 3H1 treatment as compared with 5-FU/LV alone. However, the overall survival of patients still remained unaffected [13].

Despite the fact that numerous preclinical and clinical trials are ongoing using the anti-idiotypic CEA antibody DNA vaccines against CEA-responsive tumors, the success of bringing these DNA vaccines from bench to clinic is yet very challenging. Common factors that need to overcome and increase the overall survival of patients are (a) ratio of high tumor burden in metastatic patients to the decreased immune function in these patients, which needs to overcome so as the immune effector cells can function adequately. (b) Time schedule and duration of the treatment are yet another critical factor. (c) The right choice of combinatorial treatment to reduce immunosuppression in the tumor microenvironment (TME) by preventing the infiltration of immunosuppressive cells and the production of immunosuppressive cytokines. (d) Improving their immunogenicity. (e) Nonrandomized survival data, and (f) overcoming drug-resistance mechanisms [14].

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References

  1. Zanetti BF, Ferreira CP, de Vasconcelos JRC, Han SW. scFv6.C4 DNA vaccine with fragment C of Tetanus toxin increases protective immunity against CEA-expressing tumor. Gene Ther. 2019;26:441–54.

    Article  CAS  Google Scholar 

  2. Jagadish N, Parashar D, Gupta N, Agarwal S, Purohit S, Kumar V, et al. A-kinase anchor protein 4 (AKAP4) a promising therapeutic target of colorectal cancer. J Exp Clin Cancer Res. 2015;34:142.

    Article  Google Scholar 

  3. Jagadish N, Parashar D, Gupta N, Agarwal S, Suri V, Kumar R, et al. Heat shock protein 70-2 (HSP70-2) is a novel therapeutic target for colorectal cancer and is associated with tumor growth. BMC Cancer. 2016;16:561.

    Article  Google Scholar 

  4. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2020. CA Cancer J Clin. 2020;70:7–30.

    Article  Google Scholar 

  5. Merika E, Saif MW, Katz A, Syrigos K, Morse M. Review. Colon cancer vaccines: an update. In Vivo. 2010;24:607–28.

    CAS  PubMed  Google Scholar 

  6. Denapoli PMA, Zanetti BF, Dos Santos AA, de Moraes JZ, Han SW. Preventive DNA vaccination against CEA-expressing tumors with anti-idiotypic scFv6.C4 DNA in CEA-expressing transgenic mice. Cancer Immunol Immunother. 2017;66:333–42.

    Article  CAS  Google Scholar 

  7. Spellerberg MB, Zhu D, Thompsett A, King CA, Hamblin TJ, Stevenson FK. DNA vaccines against lymphoma: promotion of anti-idiotypic antibody responses induced by single chain Fv genes by fusion to tetanus toxin fragment C. J Immunol. 1997;159:1885–92.

    CAS  PubMed  Google Scholar 

  8. McCann KJ, Godeseth R, Chudley L, Mander A, Di Genova G, Lloyd-Evans P, et al. Idiotypic DNA vaccination for the treatment of multiple myeloma: safety and immunogenicity in a phase I clinical study. Cancer Immunol Immunother. 2015;64:1021–32.

    Article  CAS  Google Scholar 

  9. Bhattacharya-Chatterjee M, Chatterjee SK, Foon KA. Anti-idiotype antibody vaccine therapy for cancer. Expert Opin Biol Ther. 2002;2:869–81.

    Article  CAS  Google Scholar 

  10. Saha A, Baral RN, Chatterjee SK, Mohanty K, Pal S, Foon KA, et al. CpG oligonucleotides enhance the tumor antigen-specific immune response of an anti-idiotype antibody-based vaccine strategy in CEA transgenic mice. Cancer Immunol Immunother. 2006;55:515–27.

    Article  Google Scholar 

  11. Saha A, Chatterjee SK. Dendritic cells pulsed with an anti-idiotype antibody mimicking Her-2/neu induced protective antitumor immunity in two lines of Her-2/neu transgenic mice. Cell Immunol. 2010;263:9–21.

    Article  CAS  Google Scholar 

  12. Foon KA, John WJ, Chakraborty M, Das R, Teitelbaum A, Garrison J, et al. Clinical and immune responses in resected colon cancer patients treated with anti-idiotype monoclonal antibody vaccine that mimics the carcinoembryonic antigen. J Clin Oncol. 1999;17:2889–5.

    Article  CAS  Google Scholar 

  13. Chong G, Bhatnagar A, Cunningham D, Cosgriff TM, Harper PG, Steward W, et al. Phase III trial of 5-fluorouracil and leucovorin plus either 3H1 anti-idiotype monoclonal antibody or placebo in patients with advanced colorectal cancer. Ann Oncol. 2006;17:437–42.

    Article  CAS  Google Scholar 

  14. Lopes A, Vandermeulen G, Preat V. Cancer DNA vaccines: current preclinical and clinical developments and future perspectives. J Exp Clin Cancer Res. 2019;38:146.

    Article  Google Scholar 

  15. King CA, Spellerberg MB, Zhu D, Rice J, Sahota SS, Thompsett AR, et al. DNA vaccines with single-chain Fv fused to fragment C of tetanus toxin induce protective immunity against lymphoma and myeloma. Nat Med. 1998;4:1281–6.

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Obstetrics and Gynecology, Medical College of Wisconsin, Milwaukee, WI, USA

    Anjali Geethadevi & Deepak Parashar

  2. Department of Biotechnology, School of Engineering and Technology, Jaipur National University, Jaipur, Rajasthan, India

    Kapilesh Jadhav

  3. Department of Biochemistry, University of Delhi, Delhi, India

    Gaurav Kumar

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Correspondence to Deepak Parashar.

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Geethadevi, A., Jadhav, K., Kumar, G. et al. scFv6.C4 DNA vaccine with fragment C of tetanus toxin increases protective immunity against CEA-expressing tumor. Gene Ther 28, 287–289 (2021). https://doi.org/10.1038/s41434-020-0161-9

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