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Autologous Dendritic Cell Based Adoptive Immunotherapy of Patients with Colorectal Cancer—A Phase I-II Study

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Pathology & Oncology Research

Abstract

Dendritic cell-based active immunotherapies of cancer patients are aimed to provoke the proliferation and differentiation of tumor-specific CD4+ and CD8+ T-lymphocytes towards protective effector cells. Isolation and in vitro differentiation of circulating blood monocytes has been established a reasonable platform for adoptively transferred DC-based immunotherapies. In the present study the safety and tolerability of vaccination by autologous tumor cell lysates (oncolysate)- or carcinoembriogenic antigen (CEA)-loaded DCs in patients with colorectal cancer was investigated in a phase I-II trial. The study included 12 patients with histologically confirmed colorectal cancer (Dukes B2-C stages). Six of the patients received oncolysate-pulsed, whereas the other six received recombinant CEA-loaded autologous DCs. The potential of the tumor antigen-loaded DCs to provoke the patient’s immune system was studied both in vivo and in vitro. The clinical outcome of the therapy evaluated after 7 years revealed that none of the six patients treated with oncolysate-loaded DCs showed relapse of colorectal cancer, whereas three out of the six patients treated with CEA-loaded DCs died because of tumor relapse. Immunization with both the oncolysate- and the CEA-loaded autologous DCs induced measurable immune responses, which could be detected in vivo by cutaneous reactions and in vitro by lymphocyte proliferation assay. Our results show that vaccination by autologous DCs loaded with autologous oncolysates containing various tumor antigens represents a well tolerated therapeutic modality in patients with colorectal cancer without any detectable adverse effects. Demonstration of the efficacy of such therapy needs further studies with increased number of patients.

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Abbreviations

5-FU:

5-Fluorouracil

AICD:

Activation-induced cell death

AIMV:

Serum free therapeutic grade cell culture medium

ALAT:

Alanine amino transferase

AMA:

Antimitochondrial antibody

ANA:

Antinuclear antibody

APC:

Antigen presenting cell

APTI:

Activated partial thromboplastin time

ASAT:

Aspartate amino transferase

CA19.9:

Cancer antigen 19.9

CEA:

Carcinoembriogenic antigen

CRC:

Colorectal carcinoma

CTL:

Cytotoxic T lymphocyte

DC:

Dendritic cell

ECOG:

Eastern cooperative oncology group/patient performance status

GM-CSF:

Granulocyte-monocyte colony-stimulating factor

HBsAg:

Hepatitis B surface antigen

HCV:

Hepatitis C virus

HIV:

Human immunodeficiency virus

HLA:

Human leukocyte antigen

IFNγ:

Interferon gamma

IL 12:

Interleukin 12

IL 2:

Interleukin 2

IL 1β:

Interleukin 1beta

IL 6:

Interleukin 6

INR:

Internation normalized ratio (coagulation)

LDH:

Lactate dehydrogenase

MDSC:

Myeloid-derived suppressor cell

MHC:

Major histocompatibility complex

NCI:

National Cancer Institute

NK cell:

Natural killer cell

PBMC:

Peripheral blood mononuclear cells

PGE2:

Prostaglandin E2

PHA:

Phytohaemagglutinin

PI:

Proliferation index

QLQ-C30:

Quality of life questionnaire-Core 30

RBC:

Red blood cell

SGOT:

Serum glutamic oxaloacetate transaminase

SGPT:

Serum glutamic pyruvate transaminase

TAA:

Tumor-associated antigen

TAM:

Tumor-associated macrophage

Tc:

T catalytic lymphocyte

Th:

T helper lymphocyte

TIL:

Tumor infiltrating lymphocytes

TNFα:

Tumor necrosis factor-alpha

WBC:

White blood cell

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Authors and Affiliations

  1. Clinical Centre for Cell Therapy, Medical and Health Science Center, University of Debrecen, Nagyerdei krt. 98, 4032, Debrecen, Hungary

    János Hunyadi & György Fazekas

  2. Institute of Oncology, Medical and Health Science Center, University of Debrecen, Nagyerdei krt. 98. Pf: 81, 4012, Debrecen, Hungary

    Csilla András, Imre Szabó, János Szántó & Kornélia Szluha

  3. Institute for Internal Medicine, Medical and Health Science Center, University of Debrecen, Debrecen, Hungary

    Sándor Sipka, Péter Kovács, Attila Kiss, Gyula Szegedi & István Altorjay

  4. Department of Surgery, Medical and Health Science Center, University of Debrecen, Debrecen, Hungary

    Péter Sápy

  5. Clinical Biochemistry and Molecular Pathology Institute, Medical and Health Science Center, University of Debrecen, Debrecen, Hungary

    Péter Antal-Szalmás

  6. Department of Pathology, Medical and Health Science Center, University of Debrecen, Debrecen, Hungary

    László Tóth

  7. Department of Immunology, Medical and Health Science Center, University of Debrecen, Debrecen, Hungary

    Éva Rajnavölgyi

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  1. János Hunyadi
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Correspondence to Imre Szabó.

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János Hunyadi and Csilla András contributed equally to this work

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Hunyadi, J., András, C., Szabó, I. et al. Autologous Dendritic Cell Based Adoptive Immunotherapy of Patients with Colorectal Cancer—A Phase I-II Study. Pathol. Oncol. Res. 20, 357–365 (2014). https://doi.org/10.1007/s12253-013-9704-3

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