A multifunctional role for adjuvant anti-4-1BB therapy in augmenting anti-tumour responses by chimeric antigen receptor T cells — ASN Events
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  2. Workshop 3: Tumour Immunology
  3. A multifunctional role for adjuvant anti-4-1BB therapy in augmenting anti-tumour responses by chimeric antigen receptor T cells

A multifunctional role for adjuvant anti-4-1BB therapy in augmenting anti-tumour responses by chimeric antigen receptor T cells (#33)

Sherly Mardiana 1 , Liza Raymond 1 , Clare Slaney 1 , Nicole Haynes 1 , Michael Kershaw 1 , Paul Beavis 1 , Phil Darcy 1
  1. Peter MacCallum Cancer Centre, Melbourne, VIC, Australia

Adoptive immunotherapy utilising chimeric antigen receptor (CAR) T cells has demonstrated high success rates in haematological cancers, with up to 90% complete remission being reported in patients with acute lymphoblastic leukaemia (ALL). However, this success is not currently transferrable to solid malignancies due to the immunosuppressive tumour microenvironment limiting CAR T cell responses1. Given that activation of the 4-1BB (CD137) pathway using an agonistic α-4-1BB antibody is known to provide strong co-stimulatory signals for augmenting and diversifying T cell responses, we hypothesised that the combination of α-4-1BB and CAR T cell therapy would result in improved anti-tumour responses. Using a human-Her2 self-antigen mouse model, we found that α-4-1BB significantly enhanced CAR T cell efficacy directed against the Her2 antigen in two different established solid tumour settings2. Investigation into the mechanism revealed increased expression of IFNγ and the proliferation marker Ki67 by tumour-infiltrating CAR T cells when combined with α-4-1BB. The importance of IFNγ was demonstrated in an experiment where synergistic effects of the combination therapy were abrogated when IFNγ was depleted. Strikingly, we also found that α-4-1BB significantly reduced host immunosuppressive cells at the tumour site including regulatory T cells (Tregs) and myeloid derived suppressor cells (MDSCs), correlating with an increased therapeutic response. Interestingly, further investigation in immunocompromised RAG-/- mice showed reduced synergistic effects following the combination therapy, suggesting some involvement of the host T cells. In addition to this, we found increased frequency of host T cells and dendritic cells in the tumour-draining lymph nodes, further supporting potential engagement of the host immune cells. We therefore conclude that α-4-1BB has a multifunctional role for enhancing CAR T cell responses including engagement of endogenous immune cells, and this combination therapy has high translational potential given α-4-1BB is currently being tested in clinical trials against various types of cancer.

  1. John LB, Devaud C, Duong CPM, Yong C, Beavis P, Haynes N, et al. Anti-PD-1 antibody therapy potently enhances the eradication of established tumors by gene-modified T cells. Clinical Cancer Research 2013;19:5636-46.
  2. Mardiana S, John LB, Henderson MA, Slaney CY, von Scheidt B, Giuffrida L, et al. A Multifunctional Role for Adjuvant Anti-4-1BB Therapy in Augmenting Antitumor Response by Chimeric Antigen Receptor T Cells. Cancer Res 2017;
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