Sphere of influence

The shape à la mode is a sphere.

Think sphere of influence. Digital sphere. Public sphere. Private sphere. Biosphere. Atmosphere. Blogosphere. This write-up concerns itself with the shape of five immunotherapies and how their structures potentially impact their activity.

Not a sphere is an adenovirus. Its shape is that of an icosahedron. An icosahedron is a 3D figure with 20 faces or flat surfaces, each composed of an equilateral triangle and 12 edges.

The outer icosahedral-shaped protein shell or capsid protects the double-stranded DNA (dsDNA) genome inside. Projecting from the capsid are fibres that mediate cell entry.

The presence of neutralising antibodies against these fibres following injection and natural infection, however, may limit the systemic activity of adenoviruses.

Adenoviruses are easily modified and armed with immunostimulatory genes for use against tumours. These anti-cancer adenoviruses are referred to as ‘oncolytic’ because they preferentially ‘lyse’ or break down tumour (onco) cells.

An unarmed oncolytic adenovirus (OA) known as Oncorine received Chinese FDA approval in 2006 for the treatment of nasopharyngeal carcinoma. No other OAs are approved.

An oncolytic adenovirus in late-stage Phase 2b clinical trials for the treatment of sarcomas and liver-predominant colorectal cancer is AdAPT-001. This virus carries a transforming growth factor-beta (TGF-β) trap.

The purpose of the TGF-β trap is to bind to and trap or neutralise the cytokine, TGF-β. Many tumours overproduce TGF-β because it suppresses the activity of the immune system that would otherwise target them for elimination.

Based on preliminary clinical results, AdAPT-001 is well tolerated and systemically active against several tumour types both on its own and in combination with checkpoint inhibitors.

Because cancer is a systemic disease that typically spreads beyond its point of origin – even if that spread is occult or micrometastatic at the time of diagnosis – systemic administration of the virus makes sense.

Like checkpoint inhibitors, chimeric antigen receptor (CAR-T) cells also benefit and potentially even cure a minority of patients (20-30%) but, in this case, only those with leukaemias, lymphomas and myelomas.

Unlike the Y-shaped checkpoint inhibitors, CAR-Ts are spherically shaped consisting of engineered T cells to which specific anti-cancer receptors like CD-19 are grafted.

When the T cell contacts a tumour cell it changes from spherical to elongated and/or flattened, which favourably reorients surface receptors, adhesion molecules and intracellular signalling molecules.

CAR-Ts are associated with two main drawbacks that limit their use. The first is cost at an estimated US $400,000 per CAR-T treatment, which puts them out of reach for many patients.

The second is the not-infrequent development of the life-threatening systemic inflammatory syndromes, cytokine storm and cytokine release syndrome.
Therefore, despite their potential upside, treatment with CAR-Ts requires vigilant close monitoring.

Another anti-cancer immunotherapeutic strategy involves the use of immunostimulatory cytokines like granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-2 (IL-2), interleukin-12 (IL-12), or interferon (IFN).

These spiral-shaped cytokines act through specific receptors that they bind to. Most cytokine receptors exist on the cell surface in an inactive state; cytokine binding triggers a conformation change of the receptor from inactive to active.

Just as AdAPT-001 carries a TGF-β trap gene that it expresses on infection of tumours, so other oncolytic viruses carry immunostimulatory cytokines like IL-12 and GM-CSF.

Approved cytokines for the treatment of cancer include interferon alpha (IFNβ) and high-dose interleukin-2 (HDIL-2). The association of these cytokines, with severe dose-limiting toxicities, does limit their use.

In cancer, macrophages, which means ‘big eaters’, are frenemies. On the one hand, they are inimical to anti-cancer treatment because they shield tumours from T-cell attack.

On the other hand, it is possible to induce these so-called tumour-associated macrophages or TAMs to switch sides or allegiances and go on the attack against tumour cells.

Anti-tumour macrophages tend to adopt a round, pancake-like shape, as they extend their ‘tentacles’ or pseudopodia and engulf tumour cells. In contrast, pro-tumour TAMs adopt an elongated shape.

RRx-001/nibrozetone is a square-shaped small molecule in late-stage clinical development with the potential to shift TAMs from pro-tumour to anti-tumour.

In addition, RRx-001/nibrozetone may protect normal tissues against the side effects from chemotherapy, radiotherapy and immunotherapy.

Cancer is classically described as a crab because of its uneven shape and infiltration of surrounding tissues. However, we imagine the shape of cancer to be more like that of a question mark because in many cases exactly how to treat it is a mystery.

The ‘shape of things to come’ in immunotherapy is that agents with different geometric configurations and non-overlapping mechanisms of action will find use in combination.

In particular, the addition of RRx-001/nibrozetone makes sense if it reduces the side effects of immunotherapies and makes them more tolerable as a result.

Ultimately, the hope is that combinatorial immunotherapy will put a period on the question mark of cancer once and for all.