Dataset Information

Phase I Trial of N-803, an IL15 Receptor Agonist, with Rituximab in Patients with Indolent Non-Hodgkin Lymphoma.

ABSTRACT:

Purpose

N-803 is an IL15 receptor superagonist complex, designed to optimize in vivo persistence and trans-presentation, thereby activating and expanding natural killer (NK) cells and CD8⁺ T cells. Monoclonal antibodies (mAbs) direct Fc receptor-bearing immune cells, including NK cells, to recognize and eliminate cancer targets. The ability of IL15R agonists to enhance tumor-targeting mAbs in patients has not been reported previously.

Patients and methods

Relapsed/refractory patients with indolent non-Hodgkin lymphoma were treated with rituximab and intravenous or subcutaneous N-803 on an open-label, dose-escalation phase I study using a 3+3 design (NCT02384954). Primary endpoint was maximum tolerated dose. Immune correlates were performed using multidimensional analysis via mass cytometry and cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq) which simultaneously measures protein and single-cell RNA expression.

Results

This immunotherapy combination was safe and well tolerated and resulted in durable clinical responses including in rituximab-refractory patients. Subcutaneous N-803 plus rituximab induced sustained proliferation, expansion, and activation of peripheral blood NK cells and CD8 T cells, with increased NK cell and T cells present 8 weeks following last N-803 treatment. CITE-seq revealed a therapy-altered NK cell molecular program, including enhancement of AP-1 transcription factor. Furthermore, the monocyte transcriptional program was remodeled with enhanced MHC expression and antigen-presentation genes.

Conclusions

N-803 combines with mAbs to enhance tumor targeting in patients, and warrants further investigation in combination with immunotherapies.

SUBMITTER: Foltz JA

PROVIDER: S-EPMC8197753 | biostudies-literature | 2021 Jun

REPOSITORIES: biostudies-literature

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Publications

Phase I Trial of N-803, an IL15 Receptor Agonist, with Rituximab in Patients with Indolent Non-Hodgkin Lymphoma.

Foltz Jennifer A JA Hess Brian T BT Bachanova Veronika V Bartlett Nancy L NL Berrien-Elliott Melissa M MM McClain Ethan E Becker-Hapak Michelle M Foster Mark M Schappe Timothy T Kahl Brad B Mehta-Shah Neha N Cashen Amanda F AF Marin Nancy D ND McDaniels Kristen K Moreno Chaz C Mosior Matthew M Gao Feng F Griffith Obi L OL Griffith Malachi M Wagner Julia A JA Epperla Narendranath N Rock Amy D AD Lee John J Petti Allegra A AA Soon-Shiong Patrick P Fehniger Todd A TA

Clinical cancer research : an official journal of the American Association for Cancer Research 20210408 12

<h4>Purpose</h4>N-803 is an IL15 receptor superagonist complex, designed to optimize <i>in vivo</i> persistence and trans-presentation, thereby activating and expanding natural killer (NK) cells and CD8<sup>+</sup> T cells. Monoclonal antibodies (mAbs) direct Fc receptor-bearing immune cells, including NK cells, to recognize and eliminate cancer targets. The ability of IL15R agonists to enhance tumor-targeting mAbs in patients has not been reported previously.<h4>Patients and methods</h4>Relapse ...[more]

PMID: 33832946

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Project description:BackgroundIn the clinical use of third-line treatment of non-Hodgkin lymphoma (NHL), the combination treatment is increasingly used due to problems such as drug resistance, and while their efficacy has been proven, whether they are economical has become a new issue. A recent trial showed copanlisib plus rituximab combination therapy (CRCT) had better efficacy in the treatment of relapsed indolent NHL (iNHL) compared to rituximab monotherapy (RM). However, the long-term cost and effectiveness of this regimen is not known. We are the first to evaluate the cost effectiveness of CRCT in third-line treatment of relapsed iNHL from the perspective of US payers.MethodsWe used a Markov model to evaluate cost and quality-adjusted life years (QALYs) which included a population from CHRONOS-3 with mean age of 62.5 years and total cycle length of 16.3 years. The cycle length was 1 month, adverse reaction rates were from CHRONOS-3, mean body surface area was referenced from published literature, cost values are referenced from published literature and Drugbank, utility values were referenced from the published literature, and the primary endpoint was the incremental cost-effectiveness ratio (ICER). The willingness to pay (WTP) threshold was set at $150,000 per QALYs, and one-way sensitivity analysis and probabilistic sensitivity analysis were used to verify the robustness of the model. All costs are expressed in 2021 dollars and costs and utilities have been calculated at a discount rate of 3% per year.ResultsCRCT and RM obtained 6.53 QALYs and 5.15 QALYs, respectively, and the ICER of CRCT vs. RM was $358,895.2/QALYs. Parameters having the greatest impact on the robustness of the model were the drug cost of copanlisib and the utility value of the progression-free survival (PFS) state. When the WTP threshold was $150,000, the probability of CRCT and RM being the most cost effective was 0.4% and 99.6% respectively.ConclusionsFrom a US payer perspective, CRCT is not cost-effective in treating relapsed iNHL at current prices compared to RM. But given its positive clinical efficacy, appropriate price discounts or assistance programs should be considered to make CRCT more affordable to patients with relapsed iNHL.

Project description:BackgroundThere is a significant association between low vitamin D levels at diagnosis of indolent B-cell lymphomas and inferior overall survival (OS). To determine whether supplemental vitamin D improves event-free survival (EFS) in these patients, we conducted a comparative double-blind study of vitamin D3 vs. placebo.MethodsIn this phase 3, randomized, double-blind, placebo-controlled trial, patients with low tumor burden follicular, marginal zone or small lymphocytic lymphoma, age 18 or older, with stage two or greater disease and no prior systemic treatment were enrolled at 7 academic cancer centers. Patients were stratified by histology and FLIPI (Follicular Lymphoma International Prognostic Index) score and randomized 2:1 to receive 2000 IU vitamin D3 or placebo daily beginning on day one with rituximab 375 mg/m2 administered weekly times four. 257 patients were assessed for participation: 24 were not eligible and 22 refused. Patients with stable disease or disease progression at week 13 counted as events; responding patients continued treatment with vitamin D or placebo until progression for up to three years. The primary endpoint was EFS, defined as the time from randomization to lack of response at week 13, initiation of a new treatment, disease progression or death. Secondary endpoints included week 13 response and OS. This trial is registered at clinicaltrials.gov, NCT03078855.Findings206 evaluable patients (135 on vitamin D and 71 on placebo) were enrolled between September 2017 and March 2022 with a median EFS follow-up of 19.6 months (IQR, 9.3-33.5). The median age was 62 years (IQR, 54-70); 118 (57%) female; 182 (89%) white. At week 13 the mean vitamin D level increased to 41.6 ng/mL (SD 10.1) in the vitamin D arm vs. remaining stable (31.3 ng/mL, SD 11.2) in the placebo arm. There was insufficient evidence of a difference in EFS between the two arms (P = 0.26): three-year EFS in the vitamin D arm was 47.7% (95% CI, 39.0-58.4) compared to 49.5% (95% CI, 37.6-65.0) in the placebo arm. There was no difference in week 13 response between the arms (both 84%). Adverse events associated with vitamin D supplementation were rare. The median OS follow-up was 35.1 months (IQR, 22.9-45.1), overall survival was 96.6% (95% CI, 93.1-98.6) and there was no significant difference between the vitamin D and placebo arms (P = 0.47).InterpretationAs tested in this study, there is no benefit to routine vitamin D supplementation in patients with indolent lymphoma treated with rituximab. These results have implications for ongoing and planned studies of vitamin D supplementation in other malignancies.FundingThis study was funded by the National Institutes of Health, National Cancer Institute grant R01CA214890.

Dataset Information

Phase I Trial of N-803, an IL15 Receptor Agonist, with Rituximab in Patients with Indolent Non-Hodgkin Lymphoma.

Purpose

Patients and methods

Results

Conclusions

Publications

Phase I Trial of N-803, an IL15 Receptor Agonist, with Rituximab in Patients with Indolent Non-Hodgkin Lymphoma.

Similar Datasets

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