Successful combined intra-tumoural immunotherapy of established murine mesotheliomas requires B cell involvement — ASN Events
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  3. Successful combined intra-tumoural immunotherapy of established murine mesotheliomas requires B cell involvement

Successful combined intra-tumoural immunotherapy of established murine mesotheliomas requires B cell involvement (#101)

Shruti Krishnan 1 , Emily Bakker 1 , Cassandra Lee 1 , Haydn T Kissick 2 , Demelza J Ireland 1 , Manfred W Beilharz 1
  1. The University of Western Australia, Crawley, WA, Australia
  2. Department of Surgery, Beth Israel Deaconess Medical Centre, Harvard Medical School, Boston, MA, USA

Introduction: Cancer immunotherapy aims to stimulate the host’s immune system to overcome immune evasion mechanisms and destroy cancer cells. We had previously developed a Timed Triple Immunotherapy (TTI) in the TGF-β secreting AE17 murine mesothelioma tumour model which targets three aspects of peripheral tolerance1.

Methods: Subcutaneous growth of non-TGF-β secreting AB1 mesothelioma tumours in BALB/c and B cell knock-out (BKO) mice (BALB/c background). TTI treatment consisted of intra-tumoural (anti-CD25mAb and 7 days daily anti-TGF-βmAb) and intra-peritoneal (anti-CTLA4mAb) injections or a novel Triple Immunotherapy Cocktail (TIC) of all three components simultaneously administered as a single intra-tumoural injection. Flow cytometric analysis of spleen and tumour draining lymph nodes (TDLNs). Tumour specific IgG detection in mouse sera by ELISA.

Results: TTI conferred tumour clearance in 100% (17/17) of BALB/c mice bearing AB1 tumours. TIC was similarly effective with 88% (15/17) tumour clearance. Cured mice showed elevated levels of tumour specific IgG antibodies at > 95 days post treatment. Time-course studies of tumour clearance showed that; (a) IgG levels were not elevated during tumour clearance, (b) B cell numbers were increased in the TDLNs and spleens during tumour clearance. An obligatory role for B cells in tumour eradication was confirmed by the employment of BKO mice in which the TIC treatment was totally ineffective.

Conclusions: Successful immunotherapies against mesothelioma tumours require simultaneous targeting of multiple immune mechanisms. Intra-tumoural delivery of monoclonal antibody combinations can effect cures without side effects. 

  1. Kissick HT, Ireland DJ, Krishnan S, Madondo M, Beilharz MW. 2012. Tumour eradication and induction of memory against murine mesothelioma by combined immunotherapy. Immunol. Cell Biol. 90(8):822-826.