Estudio del tratamiento de carcinomas gastrointestinales mediante inyecciones de células dendríticas transfectadas para producir interleuquina-12

  1. ALFARO ALEGRIA, CARLOS
Dirigida por:
  1. Ignacio Melero Bermejo Director

Universidad de defensa: Universidad de Navarra

Fecha de defensa: 05 de marzo de 2009

Tribunal:
  1. Bruno Sangro Gómez Acebo Presidente
  2. José Luis Pérez Gracia Secretario
  3. María Paloma Sánchez Mateos Rubio Vocal
  4. Juan Ruiz Echeverria Vocal
  5. Iñigo Tirapu Fernandez de la Cuesta Vocal
Departamento:
  1. (FM) Inmunología

Tipo: Tesis

Teseo: 107271 DIALNET

Resumen

Purpose: To evaluate the feasibility and safety of intratumoral injection of autologous dendritic cells (DCs) transfected with an adenovirus encoding interleukin-12 genes (AFIL-12) for patients with metastatic gastrointestinal carcinomas. Secondarily, we have evaluated biologic effects and antitumoral activity. Patients and Methods: Seventeen patients with metastatic pancreatic (n = 3), colorectal (n = 5), or primary liver (n = 9) malignancies entered the study. DCs were generated from CD14+ monocytes from leukapheresis, cultured and transfected with AFIL-12 before administration. Doses from 10 millions to 50 millions cells were escalated in three cohorts of patients. Patients received up to three doses at 21-day intervals. Results: Fifteen (88%) and 11 of 17 (65%) patients were assessable for toxicity and response, respectively. Intratumoral DC injections were mainly guided by ultrasound. Treatment was well tolerated. The most common side effects were lymphopenia, fever, and malaise. Interferon gamma and interleukin-6 serum concentrations were increased in 15 patients after each treatment, as well as peripheral blood natural killer activity in five patients. DC transfected with AFIL-12 stimulated a potent antibody response against adenoviral capsides. DC treatment induced a marked increase of infiltrating CD8+ T lymphocytes in three of 11 tumor biopsies analyzed. A partial response was observed in one patient with pancreatic carcinoma. Stable disease was observed in two patients and progression in eight patients, with two of the cases fast-progressing during treatment. In the course of the clinical trial, the use of ¹¹¹In-labeled tracing doses of DCs showed that most DCs remained inside tumor tissue, instead of migrating out. IL-8 production in malignant tissue and the responsiveness of DCs to IL-8 are a likely explanation of the clinical images, which suggest retention of DCs inside human malignant lesions. Impairment of DC migration toward lymphoid tissue could be involved in cancer immune evasion. Conclusion: Intratumoral injection of DC transfected with an adenovirus encoding interleukin-12 to patients with metastatic gastrointestinal malignancies is feasible and well tolerated. Further studies are necessary to define and increase clinical efficacy.