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Human and murine IL2 receptors differentially respond to the human-IL2 component of immunocytokines.

ABSTRACT: The humanized immunocytokine, hu14.18-IL2 (ICp), leads to the immune cell-mediated destruction of GD2-expressing tumors in mouse models, resulting in potent antitumor effects with negligible IL2-related toxicity. In contrast, when ICp is used clinically, antitumor activity is accompanied by dose-limiting IL2-related toxicities. These species-specific differences in ICp toxicity may be linked to differential binding to mouse vs. human IL2 receptors (IL2Rs). We evaluated immunocytokines genetically engineered to preferentially bind either high-affinity αβγ-IL2Rs or intermediate-affinity βγ-IL2Rs. These ICs have the IL2 fused to the C-terminus of the IgG light chains rather than the heavy chains. We found that IC35, containing intact huIL2, maintained activation of human and mouse αβγ-IL2Rs but exhibited a 20-fold reduction in the ability to stimulate human βγ-IL2Rs, with no activation of mouse βγ-IL2Rs at the concentrations tested. The reduced ability of IC35 to stimulate human βγ-IL2Rs (associated with IL2-toxicities) makes it a potential candidate for clinical trials where higher clinical IC doses might enable better tumor targeting and increased antitumor effects with less toxicity. Contrastingly, ICSK (IC with an IL2 mutein that has enhanced binding to the IL2R β-chain) showed increased activation over ICp on mouse βγ-IL2Rs, with a dose-response curve similar to that seen with IC35 on human βγ-IL2Rs. Our data suggest that ICSK might be used in mouse models to simulate the anticipated effects of IC35 in clinical testing. Understanding the differences in species-dependent IL2R activation should facilitate the design of reagents and mouse models that better simulate the potential activity of IL2-based immunotherapy in patients.

SUBMITTER: Perez Horta Z

PROVIDER: S-EPMC6492958 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Treatment of locally advanced rectal cancer includes chemotherapy, radiation, and surgery but patient responses to neoadjuvant treatment are variable. We have shown that rectal tumors are comprised of multiple genetically distinct sub-clones. Unique sub-clones within tumors may harbor mutations which contribute to inter-patient variation in response to neoadjuvant chemoradiotherapy (nCRT). Analysis of the influence of nCRT on the extent and nature of intra-tumoral genetic heterogeneity in rectal cancer may provide insights into mechanisms of resistance. Locally advanced rectal cancer patients underwent pre-treatment biopsies. At the time of surgery, tissue from the treated tumor was obtained and analyzed. Pre- and post-treatment specimens were subjected to whole exome and confirmatory deep sequencing for somatic mutations. Copy number variation was assessed using OncoScan SNP arrays. Genomic data were analyzed using PyClone to identify sub-clonal tumor population following nCRT. Alterations that persisted or were enriched in the post-treatment tumor specimen following nCRT were defined for each patient. Thirty-two samples were obtained from ten patients. PyClone identified 2 to 10 genetic sub-clones per tumor. Substantial changes in the proportions of individual sub-clones in pre- versus post-treatment tumor material were found in all patients. Resistant sub-clones recurrently contained mutations in TP53, APC, ABCA13, MUC16, and THSD4. Recurrent copy number variation was observed across multiple chromosome regions after nCRT. Pathway analysis including variant alleles and copy number changes associated with resistant sub-clones revealed significantly altered pathways, especially those linked to the APC and TP53 genes, which were the two most frequently mutated genes. Intra-tumoral heterogeneity is evident in pre-treatment rectal cancer. Following treatment, sub-clonal populations are selectively modified and enrichment of a subset of pre-treatment sub-clones is seen. Further studies are needed to define recurrent alterations at diagnosis that may contribute to resistance to nCRT.

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Human and murine IL2 receptors differentially respond to the human-IL2 component of immunocytokines.

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