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Published on: January 19, 2019
Three agonist antibodies in combination with high-dose IL-2 eradicate orthotopic kidney cancer in mice
Jennifer A Westwood1, Phillip K Darcy, Preethi Mayura Guru
1Cancer Immunology Research Program, Peter MacCallum Cancer Centre, Melbourne, Australia.
Background:
Combination immunotherapies can be effective against subcutaneous tumors in mice but the effect against orthotopic malignant disease is less well characterized. In particular, a combination of three agonist antibodies, termed Tri-mAb, consisting of anti-DR5, anti-CD40 and anti-CD137 has previously been demonstrated to eradicate a large proportion of subcutaneous renal cell carcinoma (Renca) tumors (75% long-term survival), but the effect against orthotopic disease is not known.
Purpose:
To determine the relative response of orthotopic tumors, we inoculated Renca into the kidney followed by treatment with Tri-mAb.
Results:
We found that orthotopic tumors responded much less to treatment (approximately 13% survival), but a significant improvement in survival was achieved through the addition of IL-2 to the treatment regimen (55% survival). All three agonist antibodies and high dose IL-2, 100,000 IU for up to six doses, were required. CD8+ T cells were also required for optimal anti-tumor responses. Coadministration of IL-2 led to enhanced T cell activity as demonstrated by an increased frequency of IFN-gamma-producing T cells in tumor-draining lymph nodes, which may have contributed to the observed improvement of therapy against kidney tumors.
Implications:
Responses of subcutaneous tumors to immunotherapy do not necessarily reflect how orthotopic tumors respond. The use of combination immunotherapy stimulating multiple facets of immunity and including cytokine support for T cells can induce effective anti-tumor responses against orthotopic and metastatic tumors.
Insights
Combination immunotherapy with three agonist antibodies (Tri-mAb) showed limited efficacy against orthotopic kidney tumors. Adding interleukin-2 (IL-2) significantly improved survival by enhancing T cell activity, demonstrating the importance of cytokine support in treating advanced cancers.
Area of Science:
- Immunology
- Oncology
- Cancer Therapy
Background:
- Combination immunotherapies show promise against superficial tumors.
- The efficacy of Tri-mAb (anti-DR5, anti-CD40, anti-CD137) against orthotopic kidney tumors is unknown.
- Previous studies showed Tri-mAb eradicated 75% of subcutaneous renal cell carcinoma (Renca) tumors.
Purpose of the Study:
- To evaluate the effectiveness of Tri-mAb in treating orthotopic Renca tumors.
- To determine if combination immunotherapy can overcome limitations in orthotopic models.
Main Methods:
- Renca cells were inoculated into mouse kidneys to create orthotopic tumors.
- Tumors were treated with Tri-mAb, with and without high-dose interleukin-2 (IL-2).
- Immune responses, including CD8+ T cell activity and IFN-gamma production, were assessed.
Main Results:
- Orthotopic Renca tumors showed poor response to Tri-mAb alone (13% survival).
- Adding high-dose IL-2 to Tri-mAb significantly improved survival (55%).
- Optimal response required all three antibodies, high-dose IL-2, and CD8+ T cells, with enhanced T cell activity observed.
Conclusions:
- Immunotherapy response in subcutaneous models does not predict orthotopic tumor response.
- Combination immunotherapy targeting multiple immune pathways, with cytokine support, is crucial for effective treatment of orthotopic and metastatic cancers.
- IL-2 enhances T cell activity, improving immunotherapy outcomes against kidney tumors.
