Innate Possibilities

Might modulation of the innate immune
 response turn up the heat on "cold" tumours?

It's been (another) good year for cancer immunotherapy, marked by approval of the first autologous T cell therapies for otherwise untreatable haematological cancers, additional label indications for immune checkpoint inhibitors and even glimmers of hope around personalized cancer vaccines.

All of these advances exploit adaptive immunity- the body's capacity to recognise tumours (and invading pathogens) as "not self" and to programme the immune system to bring exquisitely specific antibodies and effector cells into the attack. A downside to this biological sophistication is that mounting an adaptive immune response takes time and can be deliberately misdirected. We rely on a more primitive and less selective innate immune response as a first defence against rapidly multiplying bacteria and viruses and to prime adaptive immunity.

Bringing the innate immune response into play as a means of increasing the efficacy of cancer immunotherapy is attractive. Non-responsiveness to immune checkpoint inhibitor therapy appears to correlate with tumour inflammation, rather than with immune checkpoint expression or the degree of tumour mutation. Turning “cold” (uninflamed) tumours “hot” (inflamed) might offer patients initially refractory to immunotherapy an additional treatment option.

A signature of tumour inflammation is the presence of IFN-β, a potent cytokine, the production of which is  triggered by STING ("stimulator of interferon genes") in response to molecules ("cyclic dinucleotides"- CDNs) that signal the presence of pathogen or host double-stranded DNA. CDNs produced in response to double-stranded DNA leaking from cancer cells are capable of activating STING and triggering IFN-β production, which in turn, stimulates cancer antigen-specific T cells.

STING activation has attracted the attention of Merck and BMS, rivals in the immune checkpoint inhibitor space. Two investigational STING activators (MK-1454: Merck and ADU-S100: Aduro Biotech/Novartis) are in early clinical evaluation. Both are synthetic CDNs, designed to be more potent than "natural" CDNs but, due to their chemistry, must be delivered directly into the tumour. Spring Bank Pharmaceuticals, BMS (through the acquisition of IFM Therapeutics), iTeos Therapeutics, Invivogen and GSK are also pursuing intratumoral CDN candidates, while Nimbus Therapeutics and CuraDev Pharma are developing small molecules that may allow oral dosing.

Other components of the innate immune system are of interest to immunotherapy developers.  "Toll-like receptors" (TLRs) recognise an array of bacterial and viral debris and are known to be expressed by various cancers. Past clinical studies with TLR-directed agents have been largely disappointing, although a TLR9 agonist, IMO-2125, developed by Idera Pharmaceuticals is under evaluation in combination with immune checkpoint inhibitors in melanoma patients who have previously failed immunotherapy.

"RIG 1 (retinoic acid inducible gene)-like receptors" (RLRs) sense viral infection and can eliminate infected cells, opening the possibility that RLR activation might be exploited to directly kill cancers. RLRs are largely activated by RNA and while perhaps not easily druggable, they offer a promising enough prospect for Merck to have acquired Rigontec, a pioneer in RLR research, for a headline figure of over $500 million.

Inflammasomes are multiprotein complexes of signalling molecules and enzymes that initiate and maintain inflammatory processes in infection and autoimmune disease. Inflammasomes are activated by various "NOD-like receptors" (NLRs), the most widely studied being NLRP3, a trigger sensitive to a wide range of microbial and "damage-associated" molecules, also environmental irritants (silica, asbestos) and amyloid-β, the hallmark protein of Alzheimer's disease. NLRP3 activation may prove to be a practical means of warming up cold tumours and BMS has ambitions to begin clinical studies with an NLRP3 activator in the next 12 months.

Inflammasome activation may not be without risk, being associated with both tumour promotion and suppression in different cancers. Certain tumour-expressed TLRs appears to contribute to development of a benign tumour microenvironment and promotion of metastasis and the STING signalling pathway can contribute to tumour development.  

"Pro-inflammatory" drug development faces the general challenge of achieving an effective degree of tumour inflammation without provoking potentially life-threatening "cytokine storms" or autoimmune adverse events. A better understanding of how the innate immune response might be modulated through the targeting of STING, TLRs, RLRs, inflammasomes or other elements could conceivably lead to novel or improved treatments for a spectrum of conditions that have chronic inflammation at the heart of their pathology. 

Photo credit: Rawich at FreeDigitalPhotos.net

Promising Targets for Cancer Immunotherapy: TLRs, RLRs, and STING-Mediated Innate Immune Pathways Li, K et al. Int J Mol Sci. 2017 Feb; 18(2): 404. Online 2017 Feb 14. doi:  10.3390/ijms18020404. http://tinyurl.com/ybqlf3o3

Inflammasomes and Cancer: The Dynamic Role of the Inflammasome in Tumor Development. Kantono, M and Guo, B. Front. Immunol., Online 12 September 2017 doi.org/10.3389/fimmu.2017.01132. http://tinyurl.com/yat74boz.

Can innate immune system targets turn up the heat on 'cold' tumours? Mullard, A. Nature Reviews Drug Discovery. Vol 17, January 2018.