Abstract 5108: Overcoming roadblocks of immunotherapy in non-small cell lung cancer
Authors: Saha Tanmoy , Sengupta Shiladitya 
Published: April 2023

Abstract
Non-small cell lung cancer (NSCLC) is one of the major causes of cancer-related death worldwide. Immunotherapy has helped to increase the survival of NSCLC patients, but the therapeutic response is limited to 23-26% of patients. While many factors impact immunotherapy failure, we have focused on a few, (a) heterogeneous expression of immune checkpoints (ICs) limiting the use of single immune checkpoint inhibitor (ICI) for everyone, (b) additional ICs responsible for blocking innate immune system and lack of antigen presentation to the T cells, and (c) lack of rationally designed combination therapies.Commonly used immunotherapies for NSCLC block PD1-PDL1 interaction, but the majority of the NSCLC patient does not have high PDL1 expression indicating PD1-PDL1 as a subsidiary mode of immune evasion. So, it is necessary to include additional ICIs in order to achieve adequate objective response in all NSCLC patients. In order to investigate the immune checkpoint expression, we screened several NSCLC patient-derived tumor tissues, and only 33% of them showed high expression of PDL1, whereas 64.6% of patients had high CD47 expression. CD47, an innate immune regulator, is overexpressed in lung cancer cells and delivers an “eat-me-not” signal by binding to signal regulatory protein alpha (SIRPα) in macrophage resulting in diminishing phagocytosis and antigen presentation to the T cells.Combining anticancer drugs with immunotherapy agents has become a popular approach to achieve a less toxic and long-acting objective therapeutic response. Here, we introduce antibody conjugated drug loaded nanotherapeutics (ADNs) consisting of a targeted therapy drug, phosphatidylinositol 3-kinase (PI3K) inhibitor PI103, and decorated with two ICIs for CD47 and PDL1. The ADN particles have been designed based on classical liposomal supramolecular nanoparticles followed by surface functionalization by the specific antibody. The anti-CD47-PDL1-ADN has shown increased cellular internalization and delivery of PI103 than IgG-ADN and anti-PDL1-ADN. The anti-CD47-PDL1-ADN showed low hematotoxicity and higher cell-killing potency for the cancer cells. The bispecific anti-CD47-PDL1-ADNs can block PD1-PDL1 and SIRPα-CD47 immune checkpoint interaction, activating both the innate (macrophage) and adaptive (T cells) immune responses. Reduced tumor growth and higher survival probability have been observed in the syngeneic LLC tumor model for anti-CD47-PDL1-ADN than monotherapy and traditional immunotherapy.In summary, we have introduced a lung cancer treatment strategy that can be an effective therapy for NSCLC patients, irrespective of the PDL1 expression level. The strategy combining bispecific immunotherapy and targeted therapy for activating the innate and adaptive immune systems and delivering targeted therapy drugs can emerge as a significant advance in the treatment of NSCLC patients.
Citation Format: Tanmoy Saha, Shiladitya Sengupta. Overcoming roadblocks of immunotherapy in non-small cell lung cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5108.