{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2024,8,11]],"date-time":"2024-08-11T00:50:56Z","timestamp":1723337456046},"reference-count":45,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2021,6,16]],"date-time":"2021-06-16T00:00:00Z","timestamp":1623801600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2021,6,16]],"date-time":"2021-06-16T00:00:00Z","timestamp":1623801600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"Fundaci\u00f3n Jacinto Convit"},{"name":"Jacinto Convit World Organization, Inc."}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>ConvitVax is a personalized vaccine for the treatment of breast cancer, composed of autologous tumor cells, bacillus Calmette-Gu\u00e9rin (BCG) and low concentrations of formalin. Previous pre-clinical studies show that this therapy induces a potent activation of the immune system and achieves an effective response against tumor cells, reducing the size of the tumor and decreasing the percentage of immunosuppressive cells. In the present study, we evaluate the toxicity of ConvitVax in healthy BALB\/c mice to determine potential adverse effects related to the vaccine and each of its components. We used standard guidelines for pain, discomfort and distress recognition, continuously evaluated the site of the injection, and completed blood and urine clinical tests. Endpoint necropsy was performed, measuring the weight of organs and processing liver, kidney, thymus and lung for histological examination. Results show that the vaccine in its therapeutic dose, at 3 times its therapeutic concentration, and its individual components did not cause death or behavioral or biological changes, including any abnormalities in whole-body or organ weights, and tissue damage. These results support the safety of ConvitVax with minimal to no side-effects.<\/jats:p>","DOI":"10.1038\/s41598-021-91995-6","type":"journal-article","created":{"date-parts":[[2021,6,16]],"date-time":"2021-06-16T10:03:04Z","timestamp":1623837784000},"update-policy":"http:\/\/dx.doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Toxicity evaluation of ConvitVax breast cancer immunotherapy"],"prefix":"10.1038","volume":"11","author":[{"given":"Mar\u00eda A.","family":"Duarte C.","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jeismar M.","family":"Carballo O.","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yetsenia M.","family":"De Gouveia","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Angie","family":"Garc\u00eda","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Diana","family":"Ruiz","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Teresa","family":"Gledhill","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eglys","family":"Gonz\u00e1lez-Marcano","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ana F.","family":"Convit","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2021,6,16]]},"reference":[{"key":"91995_CR1","first-page":"1","volume":"1","author":"H Sung","year":"2021","unstructured":"Sung, H. et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 1, 1\u201341 (2021).","journal-title":"CA Cancer J. Clin."},{"key":"91995_CR2","unstructured":"World Health Organization. International Agency for Research on Cancer. https:\/\/gco.iarc.fr\/tomorrow\/en\/dataviz\/isotype?sexes=2&single_unit=500000&cancers=20. (2021)."},{"key":"91995_CR3","unstructured":"American Cancer Society. Breast Cancer Facts & Figures 2017\u20132018. 44. https:\/\/www.cancer.org\/content\/dam\/cancer-org\/research\/cancer-facts-and-statistics\/breast-cancer-facts-and-figures\/ (2017)."},{"key":"91995_CR4","unstructured":"Pisarev, M., Calandra, R., and Juvenal, G. Fisiopatolog\u00eda Endocrina: Bioqu\u00edmica y m\u00e9todos diagn\u00f3sticos. (Separatas Montpellier 2010)."},{"key":"91995_CR5","doi-asserted-by":"publisher","first-page":"270","DOI":"10.3389\/fendo.2017.00270","volume":"8","author":"R Benedetti","year":"2017","unstructured":"Benedetti, R., Dell\u2019Aversana, C., Giorgio, C., Astorri, R. & Altucci, L. Breast cancer vaccines: New insights. Front. Endocrinol. (Lausanne). 8, 270 (2017).","journal-title":"Front. Endocrinol. (Lausanne)."},{"key":"91995_CR6","doi-asserted-by":"publisher","first-page":"e58","DOI":"10.1016\/S1470-2045(13)70477-7","volume":"15","author":"G Bianchini","year":"2014","unstructured":"Bianchini, G. & Gianni, L. The immune system and response to HER2-targeted treatment in breast cancer. Lancet Oncol. 15, e58-68 (2014).","journal-title":"Lancet Oncol."},{"key":"91995_CR7","doi-asserted-by":"publisher","first-page":"397","DOI":"10.1093\/annonc\/mdy517","volume":"30","author":"S Adams","year":"2019","unstructured":"Adams, S. et al. Pembrolizumab monotherapy for previously treated metastatic triple-negative breast cancer: Cohort A of the phase II KEYNOTE-086 study. Ann. Oncol. 30, 397\u2013404 (2019).","journal-title":"Ann. Oncol."},{"key":"91995_CR8","doi-asserted-by":"publisher","first-page":"e175","DOI":"10.1016\/S1470-2045(19)30026-9","volume":"20","author":"FJ Esteva","year":"2019","unstructured":"Esteva, F. J., Hubbard-Lucey, V. M., Tang, J. & Pusztai, L. Immunotherapy and targeted therapy combinations in metastatic breast cancer. Lancet Oncol. 20, e175\u2013e186 (2019).","journal-title":"Lancet Oncol."},{"key":"91995_CR9","doi-asserted-by":"publisher","first-page":"2460","DOI":"10.1200\/JCO.2015.64.8931","volume":"34","author":"R Nanda","year":"2016","unstructured":"Nanda, R. et al. Pembrolizumab in patients with advanced triple-negative breast cancer: Phase Ib KEYNOTE-012 study. J. Clin. Oncol. 34, 2460\u20132467 (2016).","journal-title":"J. Clin. Oncol."},{"key":"91995_CR10","doi-asserted-by":"publisher","first-page":"1275","DOI":"10.1200\/JCO.2007.14.4147","volume":"26","author":"C Liedtke","year":"2008","unstructured":"Liedtke, C. et al. Response to neoadjuvant therapy and long-term survival in patients with triple-negative breast cancer. J. Clin. Oncol. 26, 1275\u20131281 (2008).","journal-title":"J. Clin. Oncol."},{"key":"91995_CR11","doi-asserted-by":"publisher","first-page":"1796","DOI":"10.1200\/JCO.2011.38.8595","volume":"30","author":"von Minckwitz","year":"2012","unstructured":"von Minckwitz, et al. Definition and impact of pathologic complete response on prognosis after neoadjuvant chemotherapy in various intrinsic breast cancer subtypes. J. Clin. Oncol. 30, 1796\u20131804 (2012).","journal-title":"J. Clin. Oncol."},{"key":"91995_CR12","doi-asserted-by":"publisher","first-page":"497","DOI":"10.1016\/S1470-2045(18)30111-6","volume":"19","author":"S Loibl","year":"2018","unstructured":"Loibl, S. et al. Addition of the PARP inhibitor veliparib plus carboplatin or carboplatin alone to standard neoadjuvant chemotherapy in triple-negative breast cancer (BrighTNess): A randomised, phase 3 trial. Lancet Oncol. 19, 497\u2013509 (2018).","journal-title":"Lancet Oncol."},{"key":"91995_CR13","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1158\/1538-7445.AM2019-2","volume":"79","author":"LM Spring","year":"2019","unstructured":"Spring, L. M. et al. Abstract GS2-03: Pathological complete response after neoadjuvant chemotherapy and impact on breast cancer recurrence and mortality, stratified by breast cancer subtypes and adjuvant chemotherapy usage: Individual patient-level meta-analyses of over 27,000 patients. Cancer Res. 79, 2\u20133 (2019).","journal-title":"Cancer Res."},{"key":"91995_CR14","first-page":"300","volume":"114","author":"J Convit","year":"2006","unstructured":"Convit, J. & Ulrich, M. Desarrollo de una autovacuna + BCG y su posible uso en el tratamiento del c\u00e1ncer. Gac. Med. Caracas. 114, 300\u2013304 (2006).","journal-title":"Gac. Med. Caracas."},{"key":"91995_CR15","first-page":"248","volume":"116","author":"J Convit","year":"2008","unstructured":"Convit, J. Inmunidad celular y su importancia en el c\u00e1ncer de la mama. Gac Med. Caracas. 116, 248\u2013249 (2008).","journal-title":"Gac Med. Caracas."},{"key":"91995_CR16","doi-asserted-by":"publisher","first-page":"1439","DOI":"10.1586\/14760584.2014.969714","volume":"13","author":"SL Kurtz","year":"2014","unstructured":"Kurtz, S. L., Ravindranathan, S. & Zaharoff, D. A. Current status of autologous breast tumor cell-based vaccines. Expert Rev. Vacc. 13, 1439\u20131445 (2014).","journal-title":"Expert Rev. Vacc."},{"key":"91995_CR17","doi-asserted-by":"publisher","first-page":"180","DOI":"10.1016\/S0022-5347(17)58737-6","volume":"116","author":"A Morales","year":"1976","unstructured":"Morales, A., Eidinger, D. & Bruce, A. W. Intracavitary Bacillus Calmette-Guerin in the treatment of superficial bladder tumors. J Urol. 116, 180\u2013183 (1976).","journal-title":"J Urol."},{"key":"91995_CR18","doi-asserted-by":"publisher","first-page":"1205","DOI":"10.1056\/NEJM199110243251703","volume":"325","author":"DL Lamm","year":"1991","unstructured":"Lamm, D. L. et al. A randomized trial of intravesical doxorubicin and immunotherapy with bacille Calmette-Gu\u00e9rin for transitional-cell carcinoma of the bladder. N. Engl. J. Med. 325, 1205\u20131209 (1991).","journal-title":"N. Engl. J. Med."},{"key":"91995_CR19","first-page":"1671","volume":"48","author":"D Berd","year":"1988","unstructured":"Berd, D. & Mastrangelo, M. J. Effect of low dose cyclophosphamide on the immune system of cancer patients: Depletion of CD4+, 2H4+ suppressor-inducer T-cells. Cancer Res. 48, 1671\u20131675 (1988).","journal-title":"Cancer Res."},{"key":"91995_CR20","doi-asserted-by":"publisher","first-page":"345","DOI":"10.1016\/S0140-6736(98)07186-4","volume":"353","author":"JB Vermorken","year":"1999","unstructured":"Vermorken, J. B. et al. Active specific immunotherapy for stage II and stage III human colon cancer: A randomised trial. Lancet 353, 345\u2013350 (1999).","journal-title":"Lancet"},{"key":"91995_CR21","doi-asserted-by":"publisher","first-page":"183","DOI":"10.1177\/107327481001700307","volume":"17","author":"H Soliman","year":"2010","unstructured":"Soliman, H. Developing an effective breast cancer vaccine. Cancer Control 17, 183\u2013190 (2010).","journal-title":"Cancer Control"},{"key":"91995_CR22","first-page":"261","volume":"17","author":"J Convit","year":"1974","unstructured":"Convit, J. et al. Elimination of Mycobacterium leprae subsequent to local in vivo activation of macrophages in lepromatous leprosy by other mycobacteria. Clin. Exp. Immunol. 17, 261\u2013265 (1974).","journal-title":"Clin. Exp. Immunol."},{"key":"91995_CR23","first-page":"263","volume":"57","author":"J Convit","year":"1986","unstructured":"Convit, J. et al. The development of a vaccination model using two microorganisms and its application in leprosy and leishmaniasis. Lepr. Rev. 57, 263\u2013273 (1986).","journal-title":"Lepr. Rev."},{"key":"91995_CR24","doi-asserted-by":"publisher","first-page":"2771","DOI":"10.1016\/j.vaccine.2006.12.043","volume":"25","author":"SF Little","year":"2007","unstructured":"Little, S. F. et al. Effect of aluminum hydroxide adjuvant and formaldehyde in the formulation of rPA anthrax vaccine. Vaccine 25, 2771\u20132777 (2007).","journal-title":"Vaccine"},{"key":"91995_CR25","doi-asserted-by":"publisher","first-page":"e0004167","DOI":"10.1371\/journal.pntd.0004167","volume":"9","author":"Y-C Fan","year":"2015","unstructured":"Fan, Y.-C., Chiu, H.-C., Chen, L.-K., Chang, G.-J.J. & Chiou, S.-S. Formalin inactivation of Japanese encephalitis virus vaccine alters the antigenicity and immunogenicity of a neutralization epitope in envelope protein domain III. PLoS Negl. Trop. Dis. 9, e0004167 (2015).","journal-title":"PLoS Negl. Trop. Dis."},{"key":"91995_CR26","doi-asserted-by":"publisher","first-page":"884","DOI":"10.1007\/s12094-015-1320-0","volume":"17","author":"J Convit","year":"2015","unstructured":"Convit, J. et al. Autologous tumor lysate\/Bacillus Calmette-Gu\u00e9rin immunotherapy as an adjuvant to conventional breast cancer therapy. Clin. Transl. Oncol. 17, 884\u2013887 (2015).","journal-title":"Clin. Transl. Oncol."},{"key":"91995_CR27","doi-asserted-by":"publisher","first-page":"20222","DOI":"10.18632\/oncotarget.25044","volume":"9","author":"MJ Godoy","year":"2018","unstructured":"Godoy, M. J., Salazar, V., Gonzalez, E. & Convit, A. F. Autologous tumor cells\/bacillus Calmette-Gu\u00e9rin\/formalin-based novel breast cancer vaccine induces an immune antitumor response. Oncotarget 9, 20222\u201320238 (2018).","journal-title":"Oncotarget"},{"key":"91995_CR28","doi-asserted-by":"publisher","first-page":"6546","DOI":"10.18632\/oncotarget.27283","volume":"10","author":"MJ Godoy","year":"2019","unstructured":"Godoy, M. J., Gonz\u00e1lez, E., Carballo, J. & Convit, A. F. Evaluation of a ConvitVax\/anti-PD-1 combined immunotherapy for breast cancer treatment. Oncotarget 10, 6546\u20136560 (2019).","journal-title":"Oncotarget"},{"key":"91995_CR29","doi-asserted-by":"publisher","first-page":"431","DOI":"10.1136\/vr.116.16.431","volume":"116","author":"DB Morton","year":"1985","unstructured":"Morton, D. B. & Griffiths, P. H. Guidelines on the recognition of pain, distress and discomfort in experimental animals and an hypothesis for assessment. Vet. Rec. 116, 431\u2013436 (1985).","journal-title":"Vet. Rec."},{"key":"91995_CR30","first-page":"1","volume":"39","author":"BA Pulaski","year":"2000","unstructured":"Pulaski, B. A. & Ostrand-Rosenberg, S. Mouse 4T1 breast tumor model. Curr. Protoc. Immunol. Curr. Protoc. Immunol. 39, 1\u201316 (2000).","journal-title":"Curr. Protoc. Immunol. Curr. Protoc. Immunol."},{"key":"91995_CR31","doi-asserted-by":"publisher","first-page":"2477","DOI":"10.1016\/j.vaccine.2016.03.100","volume":"34","author":"TN Nissen","year":"2016","unstructured":"Nissen, T. N. et al. Adverse reactions to the Bacillus Calmette-Gu\u00e9rin (BCG) vaccine in new-born infants\u2014an evaluation of the Danish strain 1331 SSI in a randomized clinical trial. Vaccine. 34, 2477\u20132482 (2016).","journal-title":"Vaccine."},{"key":"91995_CR32","doi-asserted-by":"publisher","first-page":"97","DOI":"10.1097\/01.qco.0000160895.97362.4f","volume":"18","author":"JS Bellet","year":"2005","unstructured":"Bellet, J. S. & Prose, N. S. Skin complications of Bacillus Calmette-Gu\u00e9rin immunization. Curr. Opin. Infect. Dis. 18, 97\u2013100 (2005).","journal-title":"Curr. Opin. Infect. Dis."},{"key":"91995_CR33","doi-asserted-by":"publisher","first-page":"1149","DOI":"10.3390\/ijerph15061149","volume":"15","author":"SR Lopes","year":"2018","unstructured":"Lopes, S. R. et al. Adverse events following immunization in Brazil: Age of child and vaccine-associated risk analysis using logistic regression. Int. J. Environ. Res. Public Health. 15, 1149\u20131161 (2018).","journal-title":"Int. J. Environ. Res. Public Health."},{"key":"91995_CR34","unstructured":"\u00c1lvarez, I., and Tendillo, F.J. M\u00e9todos de anestesia, analgesia y eutanasia. Man. Pr\u00e1cticas Madr. Esp. COEDI. (2010)."},{"key":"91995_CR35","doi-asserted-by":"publisher","first-page":"641","DOI":"10.1080\/01616412.1997.11740874","volume":"19","author":"W Clark","year":"1997","unstructured":"Clark, W., Lessov, N., Dixon, M. & Eckenstein, F. Monofilament intraluminal middle cerebral artery occlusion in the mouse. Neurol. Res. 19, 641\u2013648 (1997).","journal-title":"Neurol. Res."},{"key":"91995_CR36","doi-asserted-by":"publisher","first-page":"333","DOI":"10.1258\/0023677041958945","volume":"38","author":"BT Kurien","year":"2004","unstructured":"Kurien, B. T., Everds, N. E. & Scofield, R. H. Experimental animal urine collection: A review. Lab Anim. 38, 333\u2013361 (2004).","journal-title":"Lab Anim."},{"key":"91995_CR37","doi-asserted-by":"publisher","first-page":"40","DOI":"10.1016\/j.ajog.2017.12.231","volume":"219","author":"CM Chu","year":"2018","unstructured":"Chu, C. M. & Lowder, J. L. Diagnosis and treatment of urinary tract infections across age groups. Am. J. Obstet. Gynecol. 219, 40\u201351 (2018).","journal-title":"Am. J. Obstet. Gynecol."},{"key":"91995_CR38","doi-asserted-by":"publisher","first-page":"39","DOI":"10.1007\/978-1-60761-849-2_3","volume":"691","author":"L Fiette","year":"2011","unstructured":"Fiette, L. & Slaoui, M. Necropsy and sampling procedures in rodents. Methods Mol. Biol. 691, 39\u201367 (2011).","journal-title":"Methods Mol. Biol."},{"key":"91995_CR39","doi-asserted-by":"publisher","first-page":"448","DOI":"10.1080\/01926230490465874","volume":"32","author":"S Bailey","year":"2004","unstructured":"Bailey, S., Zidell, R. & Perry, R. Relationships between organ weight and body\/brain weight in the rat: What is the best analytical endpoint?. Toxicol. Pathol. 32, 448\u2013466 (2004).","journal-title":"Toxicol. Pathol."},{"key":"91995_CR40","first-page":"65","volume":"7","author":"O Fuge","year":"2015","unstructured":"Fuge, O., Vasdev, N., Allchorne, P. & Green, J. S. Immunotherapy for bladder cancer. Res. Rep. Urol. 7, 65\u201379 (2015).","journal-title":"Res. Rep. Urol."},{"key":"91995_CR41","doi-asserted-by":"publisher","first-page":"167","DOI":"10.1016\/S0302-2838(02)00260-9","volume":"42","author":"E Kaasinen","year":"2002","unstructured":"Kaasinen, E. et al. Factors explaining recurrence in patients undergoing chemoimmunotherapy regimens for frequently recurring superficial bladder carcinoma. Eur. Urol. 42, 167\u2013174 (2002).","journal-title":"Eur. Urol."},{"key":"91995_CR42","doi-asserted-by":"publisher","first-page":"e79783","DOI":"10.1371\/journal.pone.0079783","volume":"8","author":"A-H Chou","year":"2013","unstructured":"Chou, A.-H. et al. Formalin-inactivated EV71 vaccine candidate induced cross-neutralizing antibody against subgenotypes B1, B4, B5 and C4A in adult volunteers. PLoS ONE 8, e79783 (2013).","journal-title":"PLoS ONE"},{"key":"91995_CR43","unstructured":"World Health Organization. Information sheet observed rate of vaccine reactions Japanese encephalitis vaccine. http:\/\/www.who.int\/vaccine_safety\/vaccrates\/en\/index.html. (2014)."},{"key":"91995_CR44","doi-asserted-by":"publisher","first-page":"465","DOI":"10.1038\/nri2569","volume":"9","author":"TB Geijtenbeek","year":"2009","unstructured":"Geijtenbeek, T. B. & Gringhuis, S. I. Signalling through C-type lectin receptors: Shaping immune responses. Nat. Rev. Immunol. 9, 465\u2013479 (2009).","journal-title":"Nat. Rev. Immunol."},{"key":"91995_CR45","doi-asserted-by":"publisher","first-page":"60","DOI":"10.1186\/1744-8069-8-60","volume":"8","author":"F Guida","year":"2012","unstructured":"Guida, F. et al. Salvinorin A reduces mechanical allodynia and spinal neuronal hyperexcitability induced by peripheral formalin injection. Mol. Pain. 8, 60 (2012).","journal-title":"Mol. Pain."}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-91995-6.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-91995-6","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-91995-6.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,3]],"date-time":"2022-12-03T09:48:14Z","timestamp":1670060894000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-91995-6"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,6,16]]},"references-count":45,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2021,12]]}},"alternative-id":["91995"],"URL":"https:\/\/doi.org\/10.1038\/s41598-021-91995-6","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,6,16]]},"assertion":[{"value":"13 March 2020","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"3 June 2021","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"16 June 2021","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"12669"}}