PD-1/PD-L1 combination therapy in cancer treatment
Immunotherapy has transformed the treatment of cancer, it eliminates tumors by normalizing the antitumor response. Cancer immunotherapy, especially the use of immune checkpoint inhibitors, has been successful in improving the treatment landscape of malignancies. Programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) blockade therapy is a new class of anticancer immunotherapy that utilizes the body’s immune system to resist cancer and causes cancer cell death by blocking the PD-1/PD-L1 signaling pathway.
PD-1 is a class of T cell-expressed receptors that downregulates the immune system by activating the apoptosis of antigen-specific T cells, whereas PD-L1 is a transmembrane protein that suppresses the immune system by preventing foreign antigen-specific T cell accumulation and reducing antigen-specific CD8+ T cell proliferation. The interaction between PD-1 and PD-L1 acts as a co-inhibitory signal mediating T cell activation, thereby inhibiting T cell killing function and negatively regulating the human immune response. PD-1/PD-LI blockade immunotherapy has been trialed for several malignancies in the preclinical or clinical stage. Presently, Food and Drug Administration (FDA) and European Medicines Agency (EMA) have approved four PD-1 inhibitors and three PD-L1 inhibitors. Additionally, Chinese National Medical Products Administration (NMPA) has approved five PD-1 inhibitors to treat various tumors (Table 1).
Abbreviations: SC, skin cancer; NSCLC, non–small cell lung cancer; SCLC, small–cell lung cancer; RCC, renal cell carcinoma; HL, Hodgkin lymphoma; HNC, head and neck cancer; UC, urothelial carcinoma; CRC, colorectal cancer; HCC, hepatocellular carcinoma; ESC, esophageal carcinoma; MPM, malignant pleural mesothelioma; GC, gastric cancer; GEJC, gastroesophageal junction cancer; TNBC, triple-negative breast cancer; BC, bladder cancer; CC, cervical cancer; EC, endometrial cancer.
Resistance to PD-1/PD-L1 blockade therapy
PD-1/PD-L1 blockade therapy has shown potent antitumor effects. However, just as tumor cells can avoid immune evasion, cancer can resist PD-1/PD-L1 blockade treatment; thus, patients eventually could not benefit from PD-1/PD-L1 treatment.
Unresponsiveness to initial PD-1/PD-L1 blockade treatment denotes “primary resistance” to treatment. When disease progression occurs despite showing a strong initial response to treatment, the patient has “acquired resistance” to PD-1/PD-L1 blockade therapy. Both phenomena are complex, and the mechanisms causing them are multifactorial, including insufficient tumor immunogenicity, irreversible T cell exhaustion, primary resistance to IFN-γ signaling, and immunosuppressive microenvironment. In clinical studies, more than half of patients with highly positive PD-LI did not respond to PD-1/PD-L1 blockade, and PD-L1 inhibitors did not show their expected effect.
PD-1/PD-L1 blockade-based combination therapy strategies
As the mechanisms of resistance to PD-1/PD-L1 blockade continue to be investigated, strategies are emerging to prevent resistance to treatment.
Multiple strategies, including combination therapy, gut microbiome manipulation, and nano-immunotherapy, have been proposed (Figure 1). Considering the complex actors between cancer and the immune system, administering a combination of multiple agents is deemed as a more feasible approach to achieve better clinical treatment effects than single-agent administration.
Combination therapy with PD-1/PD-L1 and CTLA-4 blockers
Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), also known as CD152 (cluster of differentiation 152), is expressed in T cells and Tregs; it is only upregulated in T cells after activation. In single-agent administration, PD-1 and CTLA-4 significantly increase patients’ survival time, with a manageable safety profile. Ipilimumab, an anti-CTLA-4antibody, was approved by FDA to treat melanoma and skin cancer. In December 2021, nivolumab (anti-PD-1 antibody) and ipilimumab (anti-CTLA-4 antibody) were first used in humans, targeting two pathways. Increasing evidence indicated that CTLA-4 cooperates with PD-1/PD-L1 and has a superior antitumor immune response.
In clinical trial NCT02477826, nivolumab plus ipilimumab combination therapy was superior to platinum-doublet chemotherapy, significantly enhancing the overall response rate (ORR) from 26.9% to 45.3%and the median progression-free survival (mPFS, 7.2 months vs.5.5 months).
Patients receiving combination therapy have a significantly lower incidence of disease progression or death; the hazard ratio for disease progression or death was 0.40 (p < 0.001) in the combination therapy group versus the ipilimumab treatment group.
In an experimental study, nivolumab plus ipilimumab therapy had shown significantly longer progression-free survival than chemotherapy in patients with a high mutation load of tumors and had demonstrated promising efficacy in non–small cell lung cancer (NSCLC).
To support combination therapy research, Sino Biological has developed high-quality blocking antibodies, neutralizing antibodies, proteins, ELISA Kits, and more (Figure 2).
Combination therapy with PD-1/PD-L1 and Targeted drug EGFR
EGFR is a member of the ErbB family that binds several ligands, including EGF, amphiregulin, TGF-α, and betacellulin. Ligand binding induces the homodimerization or heterodimerization of the EGFR protein, the subsequent autophosphorylation of tyrosine, and the activation of various pathways (e.g., MAPK andPI3K/PKB). EGFR signaling also plays a crucial role in carcinogenesis and disease progression.
Trial CheckMate-012 showed a durable antitumor activity in patients with EGFR-mutated NSCLC after receiving nivolumab plus erlotinib (anti-EGFR antibody) therapy. In the NCT02013219 phase 1 study, patients with NSCLC received 150 mg of erlotinib daily for 7 days, followed by 150 mg of erlotinib daily for 7 days combined with 1200 mg of atezolizumab every 3 weeks. The ORR of this combination therapy was as high as 75% in the expansion-stage group. Meanwhile, the number of tumor-infiltrating CD8+ T cells increased in 8/13 paired biopsies after 7-day erlotinib treatment. Pneumonitis and dose-limiting toxicity were unreported. Sino Biological has developed a panel of high-quality EGFR proteins. These high-quality reagents have been validated by various methods, which provide consistent and reproducible results (Figure 3).
Conclusion
PD-1/PD-L1 blockade therapy provides a new prospect for cancer immunotherapy. The clinical effect of most combinations hinders their further application. Preclinical and clinical research continues to find an optimal combination therapy of PD-1/PD-L1 blockade and other treatments that will reduce toxic side effects and exert an antitumor immune response. Therefore, the development of new PD-1/PD-L1 drugs and combination therapy strategies will bring more benefits and survival chances to patients.
