Poster Presentation Eradicate Cancer 2020

Mechanism of enhancing the response to checkpoint inhibitors without increasing toxicity. (#103)

Angus Dalgleish 1 2 , Mark Bodman 2 , Wai Liu 2 , Alberto Fusi 2
  1. Principal, The Institute for Cancer Vaccines and Immunotherapy, London, UNITED KINGDOM, United Kingdom
  2. Institute of Infection and Immunity, St Georges University of London, London, UK, United Kingdom

Checkpoint inhibitors (CPIs) are now first line treatments in melanoma and lung cancer and have shown activity in over twenty other tumour types.  As single agents they are only effective in approximately 40% of melanoma patients, less for other tumour types.  This led to a search to biomarkers that could predict response to these agents.  To date they include PDL-1 expression, presence of micro satellite instability, high tumour antigen burden and status of the microbiome. 

Studies from mouse models have reported the absolute necessity of activated CD103+ dendritic cells and the need to activate the innate immune response, including NK cells. 

We previously reported that non-responders to a dendritic cell vaccine in metastatic melanoma had a specific proteomics signature, which included many inflammatory markers.1 A larger study using Pembrolizumab also reported the same (inflammatory) signature in non-responders.

This raises the question whether priming with anti-inflammatory agents could enhance response to CPIs.  We previously reported that patients on IMM-101 responded quickly and were more likely to have a complete response when disease relapse was treated with CPIs.2  This led to a phase II study, whose interim analysis would appear to confirm this increased response rate.  Unlike other combinations, there is no added toxicity.  Analysis of the mechanism of action of IMM-101 shows it is a stimulant for myeloid dendritic cells and activates innate cells, including NK.  It also has anti-inflammatory activity, attenuating Th-2 responses.

We previously published that Lenalidomide and Pomalidomide significantly enhance response to cancer vaccines in murine models.3  We also reported a significant survival benefit when IMM-101 was added to Gemcitabine in metastatic pancreatic cancer, versus Gemcitabine alone.  All these drugs have anti-inflammatory properties.4 

This data is presented to encourage clinical trials in other tumour types, using priming with an immune stimulant like IMM-101, plus additional use of anti-inflammatories to confirm the current evidence that these can enhance responses to CPIs without any additional toxicity.

  1. 1. Leeman H, Kaminska E, Green D, Bodman-Smith M, Gravett A, Bodman-Smith K, Copier J, Coulton G, Fusi Dalgleish AG. Serum Apolipoprotein E and Other Inflammatory Markers Can Identify Non-Responding Patients to a Dendritic Cell Vaccine. Transl Oncol. 2018 Dec 7;12(3):397-403. doi:10.1016/j.tranon.2018.11.002.
  2. 2. Dalgleish AG, Mudan S, Fusi A.Enhanced effect of checkpoint inhibitors when given after or together with IMM-101: significant responses in four advanced melanoma patients with no additional major toxicity. J Transl Med. 2018 Aug 14;16(1):227. doi: 10.1186/s12967-018-1602-8.
  3. 3. Dredge, K., Marriott, J.B., Todryk, S.M., Muller, G.W., Chen, R., Stirling, D.I. & Dalgleish, AG Protective antitumour immunity induced by a Costimulatory Thalidomide Analog in Conjunction with Whole Tumour Cell Vaccination is Mediated by Increased Th1-type Immunity. J Immunol. 2002: 168: 4914-9. doi.org/10.4049/jimmunol.168.10.4914
  4. 4. Dalgleish AG, Stebbing J, Adamson DJ, Arif SS, Bidoli P, Chang D, Cheeseman S, Diaz-Beveridge R, Fernandez-Martos C, Glynne-Jones R, Granetto C, Massuti B, McAdam K, McDermott R, Martín AJ, Papamichael D, Pazo-Cid R, Vieitez JM, Zaniboni A, Carroll KJ, Wagle S, Gaya A, Mudan SS. Randomised, open-label, phase II study of gemcitabine with and without IMM-101 for advanced pancreatic cancer. Br J Cancer. 2016 Oct 25;115(9):e16. doi: 10.1038/bjc.2016.342.