Combination of sunitinib with anti-tumor vaccination inhibits T cell priming and requires careful scheduling to achieve productive immunotherapy

Ritika Jaini, Patricia Rayman, Peter A Cohen, James H. Finke, Vincent K. Tuohy

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

Sunitinib, a protein tyrosine kinase inhibitor is the frontline therapy for renal and gastrointestinal cancers. We hypothesized that by virtue of its well documented tumor apoptosis and immune adjuvant properties, combination of Sunitinib with anti-tumor immunotherapeutics will provide synergistic inhibition of tumor growth. Our study was designed to evaluate the impact of Sunitinib on immunotherapy mediated anti-tumor immune responses and evaluate its efficacy as a combinatorial therapy with tumor targeted immunotherapeutic vaccination. Mice immunized with recombinant α-lactalbumin, a lactation protein expressed on majority of breast tumors were treated with 1 mg of Sunitinib for seven consecutive days beginning (1) concurrently, on the day of α-lactalbumin immunization or (2) sequentially, on day 9 after immunization. Ten-day lymph nodes or 21 day spleens were tested by ELISPOT assays and flow cytometry to evaluate responsiveness to α-lactalbumin immunization in presence of Sunitinib and distribution of cells involved in T cell antigen priming and proliferation in different lymphoid compartments. In addition, therapeutic efficacy of the α-lactalbumin/ Sunitinib combination was evaluated by monitoring tumor growth in the 4T1 transplanted tumor model. Our studies reveal that concurrent administration of Sunitinib with active vaccination against a targeted tumor antigen inhibits priming to the immunogen due to a drastic decrease in CD11b+CD11c+ antigen presenting cells, leading to failure of vaccination. However, sequential delivery of Sunitinib timed to avoid the priming phase of vaccination results in the desired vaccination mediated boost in immune responses. What's new? You might think that combining tumor immunotherapy with potent chemotherapy would be an ideal strategy for treating late-stage tumors. In this study, the authors found that this is not necessarily the case: the drug Sunitinib actually inhibited antigen presentation and priming when it was administered together with active immunotherapeutic vaccination. However, when delivery of the combination therapy was sequential - and timed to avoid the critical priming phase of active immunization - Sunitinib significantly enhanced the anti-tumor immune response. Combination of Sunitinib with immunotherapeutics is thus feasible, but requires careful scheduling of drug administration.

Original languageEnglish (US)
Pages (from-to)1695-1705
Number of pages11
JournalInternational Journal of Cancer
Volume134
Issue number7
DOIs
StatePublished - Apr 1 2014

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Immunotherapy
Vaccination
T-Lymphocytes
Lactalbumin
Neoplasms
Immunization
CD11c Antigens
CD11b Antigens
sunitinib
Enzyme-Linked Immunospot Assay
Gastrointestinal Neoplasms
Kidney Neoplasms
Viral Tumor Antigens
Antigen Presentation
Neoplasm Antigens
Antigen-Presenting Cells
Therapeutics
Protein Kinase Inhibitors
Growth
Lactation

Keywords

  • alpha lactalbumin
  • dendritic cells
  • immunotherapy
  • priming inhibition
  • sunitinib

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Combination of sunitinib with anti-tumor vaccination inhibits T cell priming and requires careful scheduling to achieve productive immunotherapy. / Jaini, Ritika; Rayman, Patricia; Cohen, Peter A; Finke, James H.; Tuohy, Vincent K.

In: International Journal of Cancer, Vol. 134, No. 7, 01.04.2014, p. 1695-1705.

Research output: Contribution to journalArticle

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