Augmentation versus inhibition: effects of conjunctional OX-40 receptor monoclonal antibody and IL-2 treatment on adoptive immunotherapy of advanced tumor.

Abstract

Therapeutic efficacy of adoptive immunotherapy of malignancies is proportional to the number of effector T cells transferred. Traditionally, exogenous IL-2 treatment has been used to promote the survival and function of transferred cells. Recently, we described the therapeutic effects of in vivo ligation of the costimulatory receptor, OX-40R, on activated T cells during early tumor growth. In this study, we examined the effects of IL-2 and OX-40R mAb on adoptive immunotherapy of advanced tumors. For treatment of 10-day 3-methylcholanthrene 205 pulmonary metastases, systemic transfer of 50 x 10(6) activated tumor-draining lymph node T cells resulted in >99% reduction of metastatic nodules. With either IL-2 or OX-40R mAb conjunctional treatment, only 20 x 10(6) cells were required. Advanced 10-day 3-methylcholanthrene 205 intracranial tumors could be cured by the transfer of 15 x 10(6) L-selectin(low) T cells derived from draining lymph nodes. In this situation, IL-2 administration inhibited therapeutic effects of the transferred cells. By contrast, 5 x 10(6) T cells were sufficient to cure all mice if OX-40R mAb was administrated. Studies on trafficking of systemically transferred T cells revealed that IL-2, but not OX-40R mAb, impeded tumor infiltration by T cells. Tumor regression required participation of both CD4 and CD8 T cells. Because only CD4 T cells expressed OX-40R at cell transfer, direct CD4 T cell activation is possible. Alternatively, OX-40R might be up-regulated on transferred T cells at the tumor site, rendering them reactive to the mAb. Our study suggests OX-40R mAb to be a reagent of choice to augment T cell adoptive immunotherapy in clinical trials.

• Authors: J Kjaergaard, L Peng, P A Cohen, J A Drazba, A D Weinberg, S Shu
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 167 Issue 11 Pg. 6669-77 (Dec 01 2001) ISSN: 0022-1767 [Print] United States
• PMID: 11714839 (Publication Type: Comparative Study, Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Adjuvants, Immunologic
• Antibodies, Monoclonal
• Interleukin-2
• Membrane Glycoproteins
• OX40 Ligand
• Receptors, OX40
• Receptors, Tumor Necrosis Factor
• Tnfrsf4 protein, mouse
• Tnfsf4 protein, mouse
• Tumor Necrosis Factor Receptor Superfamily, Member 7
• Tumor Necrosis Factors
• L-Selectin

Topics

• Adjuvants, Immunologic (administration & dosage)
• Animals
• Antibodies, Monoclonal (administration & dosage, therapeutic use)
• Antineoplastic Combined Chemotherapy Protocols (antagonists & inhibitors, therapeutic use)
• Brain Neoplasms (immunology, pathology, therapy)
• CD4-Positive T-Lymphocytes (metabolism, transplantation)
• CD8-Positive T-Lymphocytes (immunology, metabolism)
• Cell Movement (immunology)
• Female
• Fibrosarcoma (immunology, pathology, therapy)
• Immunotherapy, Adoptive (methods)
• Injections, Intravenous
• Injections, Subcutaneous
• Interleukin-2 (administration & dosage, adverse effects)
• L-Selectin (biosynthesis)
• Lung Neoplasms (immunology, secondary, therapy)
• Lymph Nodes (metabolism, pathology, transplantation)
• Lymphocyte Activation
• Lymphocytes, Tumor-Infiltrating (metabolism, transplantation)
• Melanoma, Experimental (immunology, pathology, therapy)
• Membrane Glycoproteins (biosynthesis, immunology)
• Mice
• Mice, Inbred C57BL
• OX40 Ligand
• Receptors, OX40
• Receptors, Tumor Necrosis Factor
• T-Lymphocytes (immunology, pathology, transplantation)
• Tumor Necrosis Factor Receptor Superfamily, Member 7 (immunology, metabolism)
• Tumor Necrosis Factors
• Up-Regulation (immunology)