Overcoming roadblocks of immunotherapy in non-small cell lung cancer

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. Commonly used immunotherapies for NSCLC blocks PD1-PDL1 interaction, but the majority of NSCLC patient does not have high PDL1 expression indicating PD1-PDL1 as a subsidiary mode of immune evasion. In order to investigate the immune checkpoint regulators, 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, delivers an “eat-me-not” signal by binding to signal regulatory protein alpha (SIRPα) in macrophages resulting in diminishing phagocytosis and antigen presentation to the T cells. Here we introduce a unified platform based on bispecific therapeutics, which can deliver multiple immune checkpoints (ICs), such as anti-PDL1 and anti-CD47, simultaneously to the tumor and activate adaptive and innate immune systems.
Additionally, the antibody-conjugated drug is a popular approach for precise delivery of the payload to the tumor; an increased specificity is expected by using a bispecific antibody. Here, we introduce dual-antibody conjugated drug-loaded nanotherapeutics (ADNs) consisting of a targeted therapy drug, PI3K inhibitor, PI103, and decorated with two ICIs for CD47 and PDL1. The ADN particles have been designed based on classical liposomal s nanoparticles followed by surface functionalization with 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 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 mono-therapy and traditional immunotherapy.