Intratumoral CCL21-gene modified dendritic cells with pembrolizumab in NSCLC

2019

Aaron Lisberg, MD

University of California, Los Angeles

Los Angeles

Currently, three immune checkpoint inhibitors are approved by the FDA for the treatment of advanced-stage NSCLC. Recently, an immunotherapy-chemotherapy combination regimen has shown to be effective in both advanced-stage squamous and non-squamous NSCLC patients. Despite this promise, immunotherapy works only in a subset of patients with advanced-stage NSCLC. There remains an unmet need to improve immunotherapy modalities such that a larger patient population may benefit from this novel treatment regimen. One hypothesis is that current checkpoint inhibitors do not work in all patients because specialized immune cells called T-cells (the target of immune checkpoint inhibitors) are unable to home in on their tumors (these tumors are referred to as “cold” tumors).

Dr. Aaron Lisberg is studying a novel combination immunotherapy approach—administering a checkpoint inhibitor, pembrolizumab, with genetically modified immune cells derived from a patient. Dendritic cells are immune cells that help other immune cells such as T-cells in identifying and homing in on a cancer. Dr. Lisberg’s laboratory will genetically manipulate a patient’s dendritic cells to artificially produce a protein called CCL21 (CCL21-DCs). He proposes that combining these CCL21-DCs will help recruit T cells to a patient’s tumor and make them responsive to the immune checkpoint inhibitor (turning a cold tumor into a hot one).

Research Summary

Lung cancer is the leading cause of cancer-related mortality in the United States, leading to more deaths than the next three cancers combined. Although immunotherapy, a class of therapy aimed at enabling a patient’s own immune system to fight cancer, has revolutionized cancer therapy, the majority of patients with non-small cell lung cancer (NSCLC) still do not derive benefit. As a result, there is an urgent need to identify immunotherapeutic approaches that will benefit a greater number of NSCLC patients.

Proposed is a three-year research career development plan formulated on a clinical trial that is evaluating a novel combination of immunotherapies, genetically modified immune cells plus an immune checkpoint inhibitor, for the treatment of metastatic NSCLC. It is hypothesized that this therapeutic approach will transform a patient’s tumor into a lymph node-like environment, enabling the immune system to identify the tumor as foreign and eradicate it, resulting in an effective immunotherapeutic approach for patients. Samples from patients in the trial will also be evaluated via additional scientific experimental methods to further elucidate alterations in patients' immunologic pathways as a result of therapy.

This novel therapeutic approach has the potential to directly benefit 70% of patients with newly diagnosed metastatic NSCLC or approximately 60,000 people in the United States per year. If proven to be effective, this approach may improve the treatment of other malignancies, which has the potential to benefit an even greater number of patients.

Technical Abstract

Effective immunotherapy options are lacking for patients with advanced non-small cell lung cancer (NSCLC) and programmed cell death-ligand 1 (PD-L1) expression <50%. One commonly proposed reason for the lack of efficacy of PD-(L)1 agents in these patients is the absence of tumor infiltrating lymphocytes. This leads to the rationale to develop therapies that could recruit T cells to the site of the tumor, such as in situ vaccination with intratumoral (IT) injection of functional antigen presenting cells. One potential approach to IT vaccination, which could convert tumor sites into a lymph node-like environment, is the injection of autologous dendritic cells (DCs) transduced with an adenoviral (Ad) vector expressing chemokine (C-C motif) ligand 21 (CCL21), a chemokine known to (1) facilitate T lymphocyte activation and (2) promote co-localization of T lymphocytes and DCs.

Design

Phase I dose escalation, multi-cohort trial, followed by dose expansion evaluating IT Ad-CCL21-DC plus pembrolizumab. Maximum 24 patients (9-12 escalation + 12 expansion) with stage IV NSCLC will be evaluated who have tumors accessible for IT injection, are treatment naïve, and have PD-L1 expression <50%. Administration of three autologous CCL21-DC IT injections (days 0/21/42) plus pembrolizumab, followed by q3wk pembrolizumab up to 1 year. Dose escalation primary objectives are safety and determination of maximum tolerated dose of IT CCL21-DC when combined with pembrolizumab. Dose expansion primary objective is objective response rate of CCL21-DC plus pembrolizumab. To evaluate the resulting immunological changes (a) mass cytometry (CyTOF) and (b) multiplex immunofluorescence (MIF) will be performed on trial specimens.

Intratumoral CCL21-gene modified dendritic cells with pembrolizumab in NSCLC

Design

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