Combination of Bempegaldesleukin and Anti-CTLA-4 Prevents Metastatic Dissemination After Primary Resection or Radiotherapy in a Preclinical Model of Non-Small Cell Lung Cancer.

Amber M Bates,Luke M Zangl,Ian Arthur,Paul A Clark,Zachary S Morris,Raghava N Sriramaneni,Ryan J Brown,Peter M Carlson,Gustavo A Sosa,Trang Le,Ravi B Patel,Alexander A Pieper,Kyungmann Kim

doi:10.3389/fonc.2021.645352

Amber M Bates, Luke M Zangl + Show 11 more

Open Access

https://doi.org/10.3389/fonc.2021.645352

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Abstract

Surgical resection or hypo-fractionated radiation therapy (RT) in early-stage non-small cell lung cancer (NSCLC) achieves local tumor control, but metastatic relapse remains a challenge. We hypothesized that immunotherapy with anti-CTLA-4 and bempegaldesleukin (BEMPEG; NKTR-214), a CD122-preferential IL2 pathway agonist, after primary tumor RT or resection would reduce metastases in a syngeneic murine NSCLC model. Mice bearing Lewis Lung Carcinoma (LLC) tumors were treated with combinations of BEMPEG, anti-CTLA-4, and primary tumor treatment (surgical resection or RT). Primary tumor size, mouse survival, and metastatic disease at the time of death were assessed. Flow cytometry, qRT-PCR, and cytokine analyses were performed on tumor specimens. All mice treated with RT or surgical resection of primary tumor alone succumbed to metastatic disease, and all mice treated with BEMPEG and/or anti-CTLA-4 succumbed to primary tumor local progression. The combination of primary tumor RT or resection and BEMPEG and anti-CTLA-4 reduced spontaneous metastasis and improved survival without any noted toxicity. Flow cytometric immunoprofiling of primary tumors revealed increased CD8 T and NK cells and decreased T-regulatory cells with the combination of BEMPEG, anti-CTLA-4, and RT compared to RT alone. Increased expression of genes associated with tumor cell immune susceptibility, immune cell recruitment, and cytotoxic T lymphocyte activation were observed in tumors of mice treated with BEMPEG, anti-CTLA-4, and RT. The combination of BEMPEG and anti-CTLA-4 with primary tumor RT or resection enabled effective control of local and metastatic disease in a preclinical murine NSCLC model. This therapeutic combination has important translational potential for patients with early-stage NSCLC and other cancers.

Highlights

Improvements in early detection [1,2,3,4] as well as advancements in surgery and radiation therapy (RT) have led to primary tumor control rates > 90% in early-stage non-small cell lung cancer (NSCLC) [5,6,7,8,9,10]
When local treatment was combined with BEMPEG and anti-CTLA-4, survival was significantly improved compared to RT or surgery alone (Figures 1A–D)
At day 90, 33% (4/12) of mice treated with BEMPEG, anti-CTLA-4, and RT were alive, while only 8% (1/12) of mice treated with RT and BEMPEG and 8% (1/12) of mice treated with RT and anti-CTLA-4 remained

Summary

Introduction

Improvements in early detection [1,2,3,4] as well as advancements in surgery and radiation therapy (RT) have led to primary tumor control rates > 90% in early-stage non-small cell lung cancer (NSCLC) [5,6,7,8,9,10]. Despite these improvements, the 5-year survival for patients with localized NSCLC remains below 60% [11] because many patients achieving primary tumor control experience regional or metastatic recurrence of disease [12, 13]. Clinical use of high-dose IL2 is limited due to its toxicity and short half-life [22, 24]

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