7:02 PM
 | 
Jun 08, 2018
 |  BioCentury  |  Product Development

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 were PD-L1-positive at baseline.

But Nektar and partner Bristol-Myers Squibb Co. will move into Phase III first in melanoma with NKTR-214 plus Opdivo nivolumab, followed by first-line renal cell carcinoma (RCC) and cisplatin-ineligible urothelial carcinoma. These are indications where checkpoint inhibitors are approved and produce substantial responses, which may make demonstrating an additive effect for the cytokine a high hurdle to clear.

N-803 is in Phase II development for non-small cell lung cancer (NSCLC), including a Phase II study in NSCLC that has progressed after responding to a PD-1 inhibitor. It also is in testing in combination with other immunotherapies in bladder, pancreatic, head and neck, breast, colorectal, liver, chordoma and hematologic cancer indications.

Posters with early data for Armo Biosciences Inc.’s pegilodecakin (AM0010) showed an alternative cytokine approach could also be effective in augmenting the efficacy of PD-1 inhibitors.

Pegilodecakin is a long-acting, pegylated form of recombinant IL-10 that stimulates a different population of cancer-fighting immune cells than are stimulated by cytokines that signal through the IL-2 intermediate-affinity receptor.

Armo is being acquired by Eli Lilly and Co. in a $1.6 billion deal expected to close this quarter.

While Armo’s data for pegilodecakin plus PD-1 inhibitors also showed better response rates than would be expected for PD-1 inhibitor monotherapy, the oncologists who spoke with BioCentury wanted to see more data on how the molecule achieves its effects.

Because endogenous IL-10 has an immunosuppressive profile, they were unsure how to interpret the clinical results in cancer. In the absence of a full biological explanation for how AM0010 fights tumors, they had less confidence in its ability to potentiate checkpoint inhibitors without confirmation in larger studies.

Data for two Phase II studies of pegilodecakin in combination with anti-PD-1 mAbs are expected late this year.

Merck KGaA presented yet another alternative approach at ASCO that involved blocking rather than stimulating cytokine signaling (see “Two in One”).


Sidebar: Two in one

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