Efficacy and mechanisms of action of rmB7.2-Ig as an antitumor agent in combination with Adriamycin and Cytoxan chemotherapy

Clin Immunol. 2001 Dec;101(3):303-14. doi: 10.1006/clim.2001.5123.

Abstract

The efficacy of chemotherapy for cancer is often limited by toxicity. Immune approaches to cancer immunotherapy, while promising for specificity and long-term protection, have not typically proven potent enough to generate significant therapeutic responses. We have shown therapeutic benefit using recombinant murine B7.2-Ig (rmB7.2-Ig) in murine tumor models. Efficacy was dependent on immune activity and was not associated with toxicity. Recently, the efficacy of rmB7.2-Ig was demonstrated in leukemia tumor models in combination with chemotherapeutic agents. To further explore the potential of this approach, we evaluated the efficacy in solid tumor models of rmB7.2-Ig given in combination with chemotherapeutics commonly used in clinical practice, testing the effects of dose and schedule. RmB7.2-Ig in combination with some chemotherapeutics enhances the activity and efficacy of reduced chemotherapeutic doses. However, the relative timing of chemotherapy and rmB7.2-Ig dosing can be important. Investigation of mechanisms of action based on histological studies suggests that inflammatory as well as T cell mechanisms comprise the response. Additional studies of mice deleted of B7.1, B7.2, and CTLA-4 suggest that the enhanced response induced by rmB7.2-Ig may not be mediated through CD28 ligation alone. The efficacy suggests potential for recombinant human B7.2-Ig as an adjuvant to chemotherapy in promoting immune-mediated mechanisms to augment the activity of chemotherapy.

MeSH terms

  • Animals
  • Antigens, CD / immunology
  • Antigens, CD / therapeutic use*
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Apoptosis / drug effects
  • B7-2 Antigen
  • Combined Modality Therapy
  • Cyclophosphamide / administration & dosage
  • Doxorubicin / administration & dosage
  • Humans
  • Immunoglobulin Heavy Chains / immunology
  • Immunoglobulin Heavy Chains / therapeutic use*
  • Immunotherapy*
  • Membrane Glycoproteins / immunology
  • Membrane Glycoproteins / pharmacokinetics
  • Membrane Glycoproteins / therapeutic use*
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Neoplasms, Experimental / immunology
  • Neoplasms, Experimental / pathology
  • Neoplasms, Experimental / therapy*
  • Recombinant Fusion Proteins / immunology
  • Recombinant Fusion Proteins / pharmacokinetics
  • Recombinant Fusion Proteins / therapeutic use

Substances

  • Antigens, CD
  • B7-2 Antigen
  • CD86 protein, human
  • Cd86 protein, mouse
  • Immunoglobulin Heavy Chains
  • Membrane Glycoproteins
  • Recombinant Fusion Proteins
  • Doxorubicin
  • Cyclophosphamide