Clinical trial NCT03450044: Immunogenicity and Safety of DCs in Breast Cancer
Official title: Immunogenicity and Safety of Autologous Dendritic Cells in Patients With Breast Cancer Treated With Neoadjuvant Chemotherapy.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Breast Cancer Female
Keywords: Chemotherapy
Breast Cancer
Dendritic cells
Immunotherapy
Doxorubicine
Lead sponsor: Fundación Salud de los Andes
Sponsor class: OTHER
Collaborators: name: Universidad Nacional de Colombia
name: Instituto Colombiano para el Desarrollo de la Ciencia y la Tecnología (COLCIENCIAS)
First posted: 2018-03-01
Enrollment: 15
Sex: FEMALE
Minimum age (years): 30
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Detailed description: The Fundación Salud de los Andes in the framework of a strategic alliance with the National University of Colombia has been working in the planning and development of a clinical trial in Colombia that promotes the search for new therapeutic alternatives for cancer patients. As a translational medicine project, it aims to make the laboratory findings available to the patient. This study explores the combination of immunotherapy (cell therapy) with chemotherapy, in order to obtain better results in the therapeutic management of tumors in patients with breast cancer.

Problem:

Breast cancer is a pathology that in recent years has increased vertiginously its incidence globally. Given the advanced state in which this tumor is usually diagnosed in our environment, the prognosis is seriously compromised, which has led to the current breast cancer represents a major public health problem in Colombia. The established therapies for the management of patients with this type of tumors such as chemotherapy, radio-therapy or surgery, are effective to reduce much of the established tumor mass, but fail to eliminate residual cancer cells, so - often - these treatments cannot prevent the recurrence of the disease. In addition to the above, the quality of life of the patients treated is strongly affected by the toxicity of these treatments on healthy tissues and their undesirable effects, which frequently affects poor adherence to treatment. That is why it is necessary to search for new therapeutic alternatives that are more specific to the tumor and that are better tolerated by patients. Due to the high specificity of the immune system for the recognition of tumors, different modalities of immune therapy for tumor control are currently being explored, which seek to enhance the performance of the patient's defense system so that a cytotoxic and memory response is established against them. tumor cells.

Type of study Clinical Trial Phase I / II.

Methodology:

Patients who attend the consultation due to their mammary pathology for the start of neo-adjuvant chemotherapy will be pre-selected to participate in the study. The participation of the volunteers will be subject to compliance with the inclusion and exclusion criteria defined for the study, as well as the signing of the informed consent. The participants will be randomly distributed into two groups.

PATIENT GROUPS As part of the clinical evaluation at the entrance of the study, a battery of laboratory tests (basic and specific to the trial) will be carried out. Subsequent to the corroboration of compliance with the inclusion criteria, patients will be randomly assigned to one of the two study groups: The first group (A) will be the negative control group, which includes patients who will receive only the standardized chemotherapy treatment for the pathology. The second group (B) will consist of those patients who were randomly selected to receive the adoptive transfer of mature autologous DCs in combination with the neo-adjuvant chemotherapy. In this way, the total of 30 patients will be distributed as follows: 15 patients for group A and 15 patients for group B.

The patients of group B will undergo an apheresis procedure in order to obtain a sample enriched in peripheral blood monocytes from which monocytes will be purified for the production of DCs. The generation of DCs will be carried out under strict conditions of Good Clinical Practices and Good Laboratory Practices.

The adoptive transfer will be carried out concomitantly with the neo-adjuvant chemotherapy treatment (eight and 15 days after chemotherapy dose for a total of 6 injections with autologous DCs).

In the period of application of the doses, a permanent clinical evaluation will be carried out to the patients, to register possible adverse effects (evaluation of the safety of the adoptive transfer of autologous DCs). The effect on the immune response of autologous DCs transferred to patients on chemotherapy vs. the effect on the immune response of chemotherapy without transfer, will be analyzed in each patient before and after chemotherapy using the state of the art of immunological techniques with which will measure the extent of anti-tumor CD8+ T cells expansion (evaluation of the immunogenicity of the adoptive transfer of autologous DCs).

Participating Institutions:

Fundación Salud de los Andes Research Group in Immunology and Clinical Oncology - GIIOC

National University of Colombia - Bogotá. School of Medicine Immunology and Translational Medicine Group Departments of Microbiology and Pathology

Other collaborating institutions:

Clínica del Seno Hospital Universitario Nacional Instituto Nacional de Cancerología Oncocare

Eligibility criteria: Inclusion criteria:

* 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.

Exclusion criteria:

* 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).
* Metastasis to the central nervous system at the time of inclusion in the study.
* 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.

Primary outcomes:
measure: Adverse effects
timeFrame: One year after innoculation
Secondary outcomes:
Other outcomes:
Locations:
city: Bogota
country: Colombia
facility: Fundación Salud de los Andes
state: Cundinamarca
Study officials:
affiliation: CEO
name: Fabio Méndez, MD
role: STUDY_CHAIR
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