Immunogenicity and Safety of DCs in Breast Cancer

NCT03450044 | Completed Phase 1 DMC

• 1 other identifier: TEBICA-001
• Study Type: interventional
• Target: 15
• Locations: 1 country
• Sites: 1

Brief Summary

This study aims to evaluate for the first time in Colombia the immunogenicity and safety of autologous DCs as enhancers of the immune response in patients with ductal breast cancer who, prior to surgical resection of the tumor, will receive neo-adjuvant chemotherapy with Doxorubicin and Cyclophosphamide. concomitantly with the transfer of autologous DCs. This clinical trial is based on the concept proposed in countries like France more than a decade ago, that chemotherapy or radiotherapy cause the tumor cells to release certain signals that favor the activation of the immune system against cancer. Therefore, the combined use of chemotherapy with vaccination with dendritic cells would provide the immune system with greater antitumor response capacity, taking advantage of the release of said signals to initiate a series of processes that would be reflected in the activation of T lymphocytes capable of destroying the remaining cells of the tumor. To determine the specificity of the response evoked by the adoptive transfer of autologous DCs, in each patient the degree of recognition of the tumor by the immune system before and after said procedure will be evaluated. These results will be compared with those of patients who participated in a control group. Hypothesis Adoptive transfer of autologous DCs generated in vitro, in patients with stage IIA-IV breast cancer who receive neoadjuvant therapy with Doxorubicin and Cyclophosphamide, is a safe procedure that stimulates anti-tumor immune responses in treated patients. Principal aim: To evaluate the safety and immunogenicity of the use of DCs when used in patients with stage IIA-IV breast cancer in association with neo-adjuvant chemotherapy with Doxorubicin/Cyclophosphamide. Specific aims:

• Generate immuno-competent dendritic cells in conditions of Good Clinical Practice and Good Laboratory Practices.
• Determine in each patient the immunological status of specific T lymphocytes against tumor antigens, before and after chemotherapy, in order to demonstrate whether the adoptive transfer of DCs favors the anti-tumor immune response.
• Register in patients with breast cancer in neo-adjuvant chemotherapy the class and frequency of adverse effects that could be generated as a result of the adoptive transfer of autologous DCs.

Conditions

Breast Cancer Female

Keywords

Chemotherapy; Breast Cancer; Dendritic cells; Immunotherapy; Doxorubicine

Outcome Measures

Primary Outcomes (1)

• Adverse effects

  Number of participants with treatment-related adverse events as associated with DCs inoculation assessed by CTCAE v4.0

  One year after innoculation

Study Arms (2)

Vaccinated

EXPERIMENTAL

Transfer of autologous dendritic cells interspersed with chemotherapy doses

Biological: Dendritic cells

Control

NO INTERVENTION

Control patients who follow their basic treatment with chemotherapy with the A/C scheme

Interventions

Dendritic cells BIOLOGICAL

Adoptive transfer of autologous DCs

Vaccinated

Eligibility Criteria

• Age: 30 Years - 65 Years
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Women between 30 and 65 years old.
• Patients who have histologically confirmed primary invasive ductal carcinoma of the breast.
• Patients who, at the time of their evaluation, present a breast cancer with TNM classification: IIA, IIB, IIIA, IIIB, IIIC or IV; in whom the breast-tumor relationship is not satisfactory for the surgical procedure, so that they will receive neo-adjuvant chemotherapy with Doxorubicin and Cyclophosphamide for at least 3 cycles.
• Patients who voluntarily agree to enter the proposed immunotherapy scheme.
• Absence of second malignant disease with the exception of a cervical carcinoma or a treated basal cell carcinoma.
• Normal blood, kidney function and hepatic function (neutrophil count 1000 / mm3, lymphocyte count 500 / mm3, hemoglobin 8mg / dl, and platelet count 150,000 / mm3, serum creatinine 1.5mg / dl, BUN 50mg / dl, aminotransferases 2 times of normal value and bilirubin 2.0mg / dl).
• Karnofsky higher than 70% or ECOG 0 to 1.
• Life expectancy greater than three months.
• Ability to understand informed consent.
• Have a weight greater than 50 Kilos at the time of apheresis.

You may not qualify if:

• Patients who are pregnant or breast-feeding.
• Patients who have received some type of therapy as treatment for their tumor pathology in the breast, prior to the start of the trial (radiotherapy, chemotherapy, immunotherapy or gene therapy).
• Active autoimmune disease requiring treatment or history of autoimmune disease, which could be exacerbated by treatment. Patients with endocrine disease controlled by replacement therapy may be included, including thyroid disease, adrenal disease and vitiligo.
• Presence of a chronic or acute infection, such as HIV, viral hepatitis or tuberculosis, before or after the signing of the informed consent.
• Use of immunosuppressant within 4 weeks prior to the trial (eg corticosteroids), such as azathioprine, prednisone or cyclosporine A. The use of local steroids (topical, nasal or inhaled) may be acceptable.
• Patients with eczema, history of eczema or other eczematous skin disorders or those with acute or chronic exfoliative skin condition (eg atopic dermatitis, burns, impetigo, varicella zoster, severe acne or open wounds).
• Any disease that could interfere with the patient's ability to carry out the treatment (eg, Crohn's disease, ulcerative colitis or active diverticulitis, severe respiratory, cardiovascular, neurological, infectious disease or uncontrolled metabolic disease), including diseases of the psychiatric type.
• Clinically significant cardiomyopathy, which requires treatment.
• Splenectomized patients.
• Patients who do not receive the neo-adjuvant chemotherapy regimen with Doxorubicin and Cyclophosphamide for three cycles.
• Patients who have had an excisional biopsy.

Sponsors & Collaborators

• Fundación Salud de los Andes: lead
• Universidad Nacional de Colombia: collaborator
• Instituto Colombiano para el Desarrollo de la Ciencia y la Tecnología (COLCIENCIAS): collaborator

Study Sites (1)

Fundación Salud de los Andes

Bogota, Cundinamarca, 111321, Colombia

Location

Related Publications (20)

• Banchereau J, Briere F, Caux C, Davoust J, Lebecque S, Liu YJ, Pulendran B, Palucka K. Immunobiology of dendritic cells. Annu Rev Immunol. 2000;18:767-811. doi: 10.1146/annurev.immunol.18.1.767.

  PMID: 10837075 BACKGROUND

• Banchereau J, Palucka AK. Dendritic cells as therapeutic vaccines against cancer. Nat Rev Immunol. 2005 Apr;5(4):296-306. doi: 10.1038/nri1592.

  PMID: 15803149 BACKGROUND

• Brossart P, Wirths S, Brugger W, Kanz L. Dendritic cells in cancer vaccines. Exp Hematol. 2001 Nov;29(11):1247-55. doi: 10.1016/s0301-472x(01)00730-5.

  PMID: 11698120 BACKGROUND

• Butterfield LH, Ribas A, Dissette VB, Amarnani SN, Vu HT, Oseguera D, Wang HJ, Elashoff RM, McBride WH, Mukherji B, Cochran AJ, Glaspy JA, Economou JS. Determinant spreading associated with clinical response in dendritic cell-based immunotherapy for malignant melanoma. Clin Cancer Res. 2003 Mar;9(3):998-1008.

  PMID: 12631598 BACKGROUND

• Chaput N, De Botton S, Obeid M, Apetoh L, Ghiringhelli F, Panaretakis T, Flament C, Zitvogel L, Kroemer G. Molecular determinants of immunogenic cell death: surface exposure of calreticulin makes the difference. J Mol Med (Berl). 2007 Oct;85(10):1069-76. doi: 10.1007/s00109-007-0214-1. Epub 2007 May 22.

  PMID: 17891368 BACKGROUND

• Dauer M, Schad K, Herten J, Junkmann J, Bauer C, Kiefl R, Endres S, Eigler A. FastDC derived from human monocytes within 48 h effectively prime tumor antigen-specific cytotoxic T cells. J Immunol Methods. 2005 Jul;302(1-2):145-55. doi: 10.1016/j.jim.2005.05.010.

  PMID: 15992809 BACKGROUND

• Dong Xda E, Ito N, Lotze MT, Demarco RA, Popovic P, Shand SH, Watkins S, Winikoff S, Brown CK, Bartlett DL, Zeh HJ 3rd. High mobility group box I (HMGB1) release from tumor cells after treatment: implications for development of targeted chemoimmunotherapy. J Immunother. 2007 Sep;30(6):596-606. doi: 10.1097/CJI.0b013e31804efc76.

  PMID: 17667523 BACKGROUND

• Figdor CG, de Vries IJ, Lesterhuis WJ, Melief CJ. Dendritic cell immunotherapy: mapping the way. Nat Med. 2004 May;10(5):475-80. doi: 10.1038/nm1039.

  PMID: 15122249 BACKGROUND

• Gabrilovich D. Mechanisms and functional significance of tumour-induced dendritic-cell defects. Nat Rev Immunol. 2004 Dec;4(12):941-52. doi: 10.1038/nri1498.

  PMID: 15573129 BACKGROUND

• Kalinski P, Okada H. Polarized dendritic cells as cancer vaccines: directing effector-type T cells to tumors. Semin Immunol. 2010 Jun;22(3):173-82. doi: 10.1016/j.smim.2010.03.002. Epub 2010 Apr 20.

  PMID: 20409732 BACKGROUND

• Mailliard RB, Wankowicz-Kalinska A, Cai Q, Wesa A, Hilkens CM, Kapsenberg ML, Kirkwood JM, Storkus WJ, Kalinski P. alpha-type-1 polarized dendritic cells: a novel immunization tool with optimized CTL-inducing activity. Cancer Res. 2004 Sep 1;64(17):5934-7. doi: 10.1158/0008-5472.CAN-04-1261.

  PMID: 15342370 BACKGROUND

• Obeid M, Tesniere A, Ghiringhelli F, Fimia GM, Apetoh L, Perfettini JL, Castedo M, Mignot G, Panaretakis T, Casares N, Metivier D, Larochette N, van Endert P, Ciccosanti F, Piacentini M, Zitvogel L, Kroemer G. Calreticulin exposure dictates the immunogenicity of cancer cell death. Nat Med. 2007 Jan;13(1):54-61. doi: 10.1038/nm1523. Epub 2006 Dec 24.

  PMID: 17187072 BACKGROUND

• Okada H, Kalinski P, Ueda R, Hoji A, Kohanbash G, Donegan TE, Mintz AH, Engh JA, Bartlett DL, Brown CK, Zeh H, Holtzman MP, Reinhart TA, Whiteside TL, Butterfield LH, Hamilton RL, Potter DM, Pollack IF, Salazar AM, Lieberman FS. Induction of CD8+ T-cell responses against novel glioma-associated antigen peptides and clinical activity by vaccinations with alpha-type 1 polarized dendritic cells and polyinosinic-polycytidylic acid stabilized by lysine and carboxymethylcellulose in patients with recurrent malignant glioma. J Clin Oncol. 2011 Jan 20;29(3):330-6. doi: 10.1200/JCO.2010.30.7744. Epub 2010 Dec 13.

  PMID: 21149657 BACKGROUND

• Pinzon-Charry A, Maxwell T, Lopez JA. Dendritic cell dysfunction in cancer: a mechanism for immunosuppression. Immunol Cell Biol. 2005 Oct;83(5):451-61. doi: 10.1111/j.1440-1711.2005.01371.x.

  PMID: 16174093 BACKGROUND

• Ramakrishnan R, Antonia S, Gabrilovich DI. Combined modality immunotherapy and chemotherapy: a new perspective. Cancer Immunol Immunother. 2008 Oct;57(10):1523-9. doi: 10.1007/s00262-008-0531-4. Epub 2008 May 17.

  PMID: 18488219 BACKGROUND

• Romero P, Cerottini JC, Waanders GA. Novel methods to monitor antigen-specific cytotoxic T-cell responses in cancer immunotherapy. Mol Med Today. 1998 Jul;4(7):305-12. doi: 10.1016/s1357-4310(98)01280-5.

  PMID: 9743992 BACKGROUND

• Zitvogel L, Apetoh L, Ghiringhelli F, Kroemer G. Immunological aspects of cancer chemotherapy. Nat Rev Immunol. 2008 Jan;8(1):59-73. doi: 10.1038/nri2216.

  PMID: 18097448 BACKGROUND

• Bernal-Estevez D, Sanchez R, Tejada RE, Parra-Lopez C. Chemotherapy and radiation therapy elicits tumor specific T cell responses in a breast cancer patient. BMC Cancer. 2016 Aug 3;16:591. doi: 10.1186/s12885-016-2625-2.

  PMID: 27484900 RESULT

• Bernal-Estevez DA, Garcia O, Sanchez R, Parra-Lopez CA. Monitoring the responsiveness of T and antigen presenting cell compartments in breast cancer patients is useful to predict clinical tumor response to neoadjuvant chemotherapy. BMC Cancer. 2018 Jan 15;18(1):77. doi: 10.1186/s12885-017-3982-1.

  PMID: 29334915 RESULT

• Bernal-Estevez DA, Ortiz Barbosa MA, Ortiz-Montero P, Cifuentes C, Sanchez R, Parra-Lopez CA. Autologous Dendritic Cells in Combination With Chemotherapy Restore Responsiveness of T Cells in Breast Cancer Patients: A Single-Arm Phase I/II Trial. Front Immunol. 2021 Aug 20;12:669965. doi: 10.3389/fimmu.2021.669965. eCollection 2021.

  PMID: 34489928 DERIVED

MeSH Terms

Conditions

Breast Neoplasms

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases

Study Officials

• Fabio Méndez, MD

  CEO

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 12, 2018
• First Posted: March 1, 2018
• Study Start: January 1, 2014
• Primary Completion: July 1, 2018
• Study Completion: August 1, 2018
• Last Updated: February 5, 2020

Record last verified: 2020-02

Data Sharing

• IPD Sharing: Will not share

Locations

CO (1)