Lung cancer immunotherapy: progress, pitfalls, and promises

Abstract

Lung cancer is the primary cause of mortality in the United States and around the globe. Therapeutic options for lung cancer treatment include surgery, radiation therapy, chemotherapy, and targeted drug therapy. Medical management is often associated with the development of treatment resistance leading to relapse. Immunotherapy is profoundly altering the approach to cancer treatment owing to its tolerable safety profile, sustained therapeutic response due to immunological memory generation, and effectiveness across a broad patient population. Different tumor-specific vaccination strategies are gaining ground in the treatment of lung cancer. Recent advances in adoptive cell therapy (CAR T, TCR, TIL), the associated clinical trials on lung cancer, and associated hurdles are discussed in this review. Recent trials on lung cancer patients (without a targetable oncogenic driver alteration) reveal significant and sustained responses when treated with programmed death-1/programmed death-ligand 1 (PD-1/PD-L1) checkpoint blockade immunotherapies. Accumulating evidence indicates that a loss of effective anti-tumor immunity is associated with lung tumor evolution. Therapeutic cancer vaccines combined with immune checkpoint inhibitors (ICI) can achieve better therapeutic effects. To this end, the present article encompasses a detailed overview of the recent developments in the immunotherapeutic landscape in targeting small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). Additionally, the review also explores the implication of nanomedicine in lung cancer immunotherapy as well as the combinatorial application of traditional therapy along with immunotherapy regimens. Finally, ongoing clinical trials, significant obstacles, and the future outlook of this treatment strategy are also highlighted to boost further research in the field.

Keywords: Adaptive cell therapy; Antibody; CAR T therapy; Cancer Vaccine; Immunomodulators; Immunotherapy; Lung Cancer; NSCLC; Nanomedicine; SCLC; TCR T therapy; TIL therapy.

Fig. 1

Genetic profiling of lung cancer (SCLC, LUAD, and LUSC) have shown changes in several oncogenes and tumor suppressor genes. Based on the total of somatic mutations, homozygous deletions, localized amplification, and substantial changes in gene expression, the values in each box represent the rates of genomic abnormalities. Other crucial proteins that mediate the pathways are also discussed. EGF, epidermal growth factor; FGF, fibroblast growth factor; GF, growth factor; DLL, deltalike; EGF, epidermal growth factor; FGF, fibroblast growth factor; GF, growth factor; HGF, hepatocyte growth factor; NRG, neuregulin; RTK, receptor tyrosine kinase. Figure reproduced with permission from Reference 39

Fig. 2

Immune interaction between T-cells, APCs, and cancer cells A. Schematic representing the mechanism of antigen-specific T cell activation. DCs play a crucial role in anti-tumor immunity due to their exceptional capacity to activate T cells following the central dogma of three signals. S1: Signal 1; S2: Signal 2; S3: Signal 3; TME: Tumor microenvironment; DC: Dendritic cell. B. Schematic showing immune interaction between T cell and APC; T cell with tumor cells. The T cell co-inhibitory and co-stimulatory molecules are shown in black and red fonts respectively. APC: Antigen presenting cell, L: Ligand

Fig. 3

Different aspects of lung cancer immunotherapy. A: Lung cancer immunotherapy by using a tumor-specific vaccine to combat cancer. B: Donor or patient T cells are collected in vitro, followed by the introduction of Chimeric Antigen Receptor (CAR) receptors and mass-produced in the lab to combat cancer. Following infusion back to the patient, the CAR T-cells attack the patient's tumor. C: Oncolytic virus and lung cancer cell oncolysis. D: Monoclonal antibodies (mAbs) may be effective against lung cancer by targeting a specific section of the cancer cell

Fig. 4

Schematic representation of CAR architectural design. A: Evolution of CAR design through generations. B. Armored CAR T-cell design and functional mechanism. C. Schematic enumerates various building components that correlate to different CAR segments that may be exploited as CAR construction components. Gen: Generation; scFv: single-chain variable fragment; AD: activation domain; Co-S1: Co-stimulatory domain 1; Co-S2: Co-stimulatory domain 2; VL: variable light; VH: variable heavy; TRUCK: T-cells Redirected towards Universal Cytokine Killing. BiTEs: Bispecific T-cell engager

Fig. 5

Schematic showing TIL and TCR T cell therapy. TCR T and TILs are isolated from the patient and multiplied in the laboratory before being reintroduced to the patient

Fig. 6

Scheme of treatment with immunotherapy in NSCLC. The algorithm helps the physician decide on the available treatments for different types of lung cancers. Their consensus sequencing techniques. PD-L1 testing and histological subtype determination should be done by a multidisciplinary team for all patients. The role of driver mutation, as shown, is important in determining treatment modalities