NKT cells can enhance Th1-based anti-tumour immunity to advanced cancers in vaccine models and in patients — ASN Events
  1. Schedule
  2. Session 10 - Autoimmunity/Cancer I
  3. NKT cells can enhance Th1-based anti-tumour immunity to advanced cancers in vaccine models and in patients

NKT cells can enhance Th1-based anti-tumour immunity to advanced cancers in vaccine models and in patients (#74)

Mark A. Exley 1 2 3 , Bindu Varghese 2 , Philip Friedlander 2 , Lydia Lynch 2 , Simon C. Yue 2 , Tetsuro Sasada 2 , Anita Giobbie-Hurder 2 , F. Stephen Hodi 2 , Jerome Ritz 2 , Steven P. Balk 2
  1. Gastroenterology, Brigham & Women's Hospital, Boston, MA, USA
  2. Harvard Medical School, Boston, MA, USA
  3. University of Manchester, Manchester, ACT, United Kingdom

Cancer patient iNKT defects are reversible in vitro.  We investigated correcting defects in models and patients. Remarkably, iNKT are required for GM-CSF-secreting tumor vaccine (‘GVax’)-induced immunity.  In transgenic prostate cancer (PCa), as in advanced PCa patients, iNKT become defective in IFNγ production, associated with chronic stimulation by tumor CD1d and putative endogenous ligand, reversed by αGalCer with IL-12.  iNKT synergize with low dose IL-12 for curative anti-tumor immunity to PCa-GVax in late-stage disease.  Tumors and uninvolved prostate were infiltrated with T cells and iNKT, which secreted enhanced IFNγ to tumor.  Immunity required all vaccine components and CD8 T cells, being partially dependent on NK and CD4 T cells.  Importantly, protected mice specifically rejected prostate tumors, confirming immune memory.  Re-challenge protection was associated with activated GranzymeB+ T cells.  CpG and αGalCer similarly synergized in a lymphoma model.

A phase 1 clinical trial was performed to reverse iNKT functional and quantitative defects in stage IIIB-IV melanoma (DF/HCC #06-432).  Residual iNKT purified to ~50% using anti-iNKT-specific mAb-magnetic microbeads were expanded ~1000X.  Expanded iNKT produced IFNγ, but little if any IL-4/IL-10.  Planned 3 iNKT infusions were completed on 9 melanoma patients, including 1 patient removed due to ineligibility.  iNKT infusions produced minimal toxicities.  4th patient onwards received GM-CSF second 2 iNKT infusions.  iNKT 'spikes' were seen in PBMC, amplified on infusions 2 and/or 3 with some patients also receiving GM-CSF.  PBMC revealed frequently increased IFNγ responses to αGC after infusions.  Neoantigen antibody responses were detected with some patients.  Candida DTH increased with 5/8 patients.  Two patients succumbed to disease at 24 and 29 months post-treatment.  Three were without progression at 53, 60 and 65 months, three had eventual treatment-responsive progression (alive at 61, 81, 85 months).  There was no clear correlation between outcome and immune parameters.  iNKT with enhanced Th1 responses have anti-tumor potential.