POC for cytokines

Cytokines are emerging as a logical combination partner to boost PD-1 responses

A body of clinical evidence is emerging that two different approaches to immune-stimulating cytokine therapies could increase efficacy of PD-1 inhibitors in both hot and cold tumors.

Oncologists who spoke to BioCentury said, taken together, data presented for Nektar Therapeutics’ NKTR-214 at the American Society of Clinical Oncology (ASCO) meeting and data published on NantWorks LLC’s N-803 suggest that cytokines that signal through a common heterodimeric receptor can increase responses to PD-1 inhibitors beyond what would be expected from the inhibitors alone.

The doctors cautioned against reading too much into the apparent decline in response rates to NKTR-214 as the trial progresses, and pointed instead to multiple signs in the data that the product is having the biological effect expected of IL-2.

Both candidates signal through the intermediate-affinity IL-2 receptor, which comprises the IL-2 receptor beta chain (CD122; IL2RB) and gamma chain (CD132; IL2RG).

Selective activation of the intermediate-affinity receptor triggers activation and proliferation of CD8+ T cells and NK cells needed to carry out an anticancer response, but spares Treg expansion and toxicities mediated by the high-affinity IL-2 receptor.

NKTR-214 is an IL-2 that contains six conjugated PEG moieties that extend half-life and release over time in a way that biases the molecule to signal through the intermediate-affinity receptor instead of the high-affinity receptor.

N-803 is a mutant version of IL-15 complexed to an Fc fusion protein of IL-15 receptor alpha chain (IL-15RA). IL-15 signals through the intermediate-affinity IL-2 receptor only in the presence of IL-15RA. Fusing IL-15 to IL-15RA keeps the needed receptor close at hand and improves the construct’s stability. NantWorks gained N-803 through last year’s acquisition of Altor Bioscience Corp. for an undisclosed sum.

“All our data suggest they are likely to benefit with deepening responses and increasing responses over time.”

Jonathan Zalevsky, Nektar

The oncologists did say that the bigger opportunity for these candidates may be in tumor types that have not typically responded well to PD-1 monotherapy. Early data showed the cytokines can flip tumors from PD-L1-negative to -positive, leading to responses comparable to those in tumors that

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