Cytokine therapy focus – riding on Nektar’s coattails

As cancer immunotherapy undergoes its next iteration interleukin-2 is hogging the limelight, and last Friday’s 22% surge in Nektar Therapeutics stock suggests that this attention might not abate any time soon.

But there are other cytokine approaches that investors might watch out for too. In hot pursuit of IL-2 comes IL-12, a well-known target that has been dogged by similar complexities, which scientists are now trying to solve. And IL-10, where the recently floated Armo Biosciences claims the lead, offers more evidence that things in the cytokine world are anything but straightforward (see table below).

The strange thing about trying to use IL-10 in oncology, where the aim is to trigger an immune response, is that until recently this was thought of as a major immunosuppressive cytokine. Indeed, IL-10 and IL-12 – a typical pro-inflammatory cytokine – have been described as having antagonistically opposing functions.

However, Armo calls IL-10 a growth factor that is essential for the activation and expansion of cytotoxic T cells. Its lead asset, AM0010, is a pegylated form of IL-10 in a phase III study in pancreatic cancer; it showed a 16% remission rate in a 21-patient phase Ib trial.

Readout of AM0010’s pivotal pancreatic cancer trial is one of the current quarter’s key binary outcome biotech events.

Selected oncology projects based on IL-10 & IL-12 signalling
Project Company Status Mechanism Detail
AM0010 (pegilodecakin) Armo Biosciences Phase III Pegylated rhIL-10 Armo claims that this stimulates expansion of CD8+ T cells
Ad-RTS-hIL-12 Ziopharm/Intrexon Phase II Intratumoural IL-12 gene therapy Adenoviral vector controlled with Rheoswitch system by veledimex
GEN-1 Celsion Phase II IL-12 gene therapy IL-12 DNA plasmid vector formed into nanoparticles with a lipopolymeric delivery system
HemaMax Neumedicines Phase II rhIL-12 Studies in acute radiation syndrome as well as CTCL
LipoVIL12 Regulon Phase II IL-12 gene therapy Uses liposome encapsulation; no longer listed in pipeline
Tavokinogene telsaplasmid Oncosec Medical Phase II IL-12 gene therapy Delivered by electroporation via Immunopulse device; Keytruda combo
EMD 521873/M9241 Merck KGaA Phase I IL-12/Ab fusion protein Ab portion meant to direct agent to regions of tumour necrosis and apoptosis 
AVR-ONC-01 Avrobio Phase I IL-12 gene therapy Ex vivo, for AML; no longer listed in pipeline
MK-1966 Merck & Co Phase I IL-10 downregulator Aims to counteract suppressive effects of IL-10, inhibiting Treg production
mRNA-2905 Moderna/Astrazeneca Preclinical mRNA encoding IL-12 Potential for combo with checkpoint inhibitor
AM0012 Armo Biosciences Preclinical rhIL-12 Potential for combo with AM0010
Immunalon Provecs Medical Preclinical IL-2, IL-12 & 4-1BBL gene therapy Intratumourally injected adenoviral vector
Source: EvaluatePharma.

The IL-10 paradox is perfectly illustrated by the fact that at one point IL-10 supplementation had been thought to have promise against Crohn’s – an autoimmune disease – and that Merck & Co’s anticancer project MK-1966 aims downregulate IL-10.

Much of AM0010’s promise lies in combinations with either Opdivo or Keytruda. This is a common theme among cytokine-based approaches, and Nektar’s 22% climb last week followed reports of two additional remissions in a trial of NKTR-214, which targets the IL-2 pathway, in combination with Opdivo.

Likewise, Oncosec hopes to broaden the scope of checkpoint blockade, attempting to make cold tumours immunogenic by priming them with IL-12. The T-cell activatory cytokine IL-12 has been described as an ideal therapeutic candidate, but – rather as is the case with IL-2 – data have so far been mixed.

Work has focused on reducing the toxicity inherent in broad immune system stimulation, for instance investigating the targeted delivery of IL-12 to make it a safer and more effective cancer therapeutic.

Oncosec’s approach is to deliver IL-12 in a pulsed manner using electroporation, and early data from a Keytruda combo in melanoma were promising (SITC – Oncosec heats up tumours, and so might competition, November 15, 2017). But the group still has a micro-cap valuation, and subsequent efforts have focused on expanding into triple-negative breast cancer and raising cash.

In even worse shape is Celsion, a company valued at just $40m. Its GEN-1 delivers IL-12 via a plasmid vector formed into nanoparticles with a lipopolymeric delivery system. The group says avoiding the frequent, large bolus injections necessary when administering IL-12 as a recombinant protein could circumvent the serious toxicities and broaden this cytokine’s use.

Gene therapy

GEN-1 is a gene therapy, an approach several groups had used to deliver IL-12. But at least two of these, Regulon’s LipoVIL12 and Avrobio’s AVR-ONC-01, appear to have been shelved, and the latter company is now focused on rare diseases.

A still prominent IL-12 gene therapy is Intrexon/Ziopharm’s Ad-RTS-hIL-12, which additionally uses the groups’ Rheoswitch, a technology aiming to switch transcriptional control on or off using the small molecule veledimex. However, frequent conference presentations notwithstanding, progress with this project has been painfully slow.

If gene therapies do not hold the key then investors might still look to Moderna/Astrazeneca’s mRNA-2905 and Merck KGaA’s M9241; the latter project, a fusion protein with an antibody-based targeting region, is in an open-label Bavencio combination trial that could generate results this year.

Meanwhile, mRNA-2905 is one the most technologically intriguing projects, comprising mRNA encoding IL-12, the aim being to express the cytokine locally in the tumour. This asset, which the companies also hope could be combined with checkpoint blockade, was highlighted when Moderna came out of stealth mode a year ago.

The start of mRNA-2905 clinical trials will be closely watched, though greater expectations likely rest with Armo, and of course any group that makes progress cracking the difficulties of IL-12 should expect its share of attention too.

To contact the writer of this story email Jacob Plieth in London at jacobp@epvantage.com or follow @JacobPlieth on Twitter

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