Humanigen Inc (HGENQ)

[bobshmob]

agmcsf pointed out an excellent new paper on the conflicted roles of GM-CSF in the immune system, especially in the lungs. Here's my amateur's take on it.

On the one hand, GM-CSF is central in maintaining immune system homeostasis in lung alveoli. It is critically important for initiation of CD8+ cell responses in the lung. Reduced GM-CSF is associated with opportunistic infections (bronchitis, nasopharyngitis, pneumonia) due to impaired GM-CSF signaling. On the other hand, it is a key player in stimulating production of immune cells that produce pro-inflammatory cytokines and of stimulating production of the pro-inflammatory cytokines themselves, leading to the "cytokine storm" that is so damaging in severe cases. GM-CSF may be involved in a positive feedback loop with CD8+ (or other T cells), with GM-CSF stimulating CD8+ production, which in turn leads to more GM-CSF, which leads to more pro-inflammatories.

Blocking GM-CSF (or GM-CSFr) is an obvious possibility for treating severe covid-19 cases, and we've seen encouraging preliminary results for mavrilimumab (in Italy) and for lenzilumab (in EINDs in the US). The theoretical MOA (blocking GM-CSF signaling should lead to reduction in pro-inflammatories) is confirmed in the blood panels and reflected in improved clinical outcomes (hopefully---that's what the RCTs are for).

But what are the consequences of knocking out such a central player in the immune respose at a time when the body is fighting off a serious infection? Both the number of CD8+ cells and their status w.r.t. immune exhaustion (Diao et al. 2020, Weiskopf et al. 2020, Ganji et al. 2020) are important. What effect would/does lenzilumab have on CD8+? And what would be the risks of blocking GM-CSF either in the viral stage of the disease (before cytokine storm) or after the haywire immune response but before the virus is cleared? That's partly what the CRTs are for. And, maybe, that's partly what makes remdesivir a good fit for lenzilumab in a combo therapy.

Others are talking about administering GM-CSF itself (not a blocker!) to prevent "hyperoxia-induced lung injury by strengthening the resistance of alveolar wall cells to apoptosis and protecting against secondary bacterial infection." [But it wasn't been shown to work in an underpowered RCT that was canceled due to slow enrollment.]