Background
Cancer immunotherapy, represented by immune checkpoint inhibitors (ICIs), has reshaped the treatment paradigm for advanced non-small cell lung cancer and small cell lung cancer. Programmed death receptor 1/programmed death receptor ligand 1 (PD-1/PD-L1) and cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) are the most common and promising targets for ICIs. Compared to ICI monotherapy, which occasionally leads to treatment resistance and has limited efficacy, dual blockade of PD-1/PD-L1 and CTLA-4 targets different stages of T cell activation, synergistically enhancing immune responses against cancer cells. This emerging dual therapy represents a new direction in cancer immunotherapy, but while improving efficacy, it may also increase the risk of drug-related adverse reactions. The recent emergence of bispecific antibodies has made this dual targeting more feasible, aiming to mitigate toxicity without compromising efficacy.
On July 27, 2024, Wu Yijun/Kang Kai from the Institute of Thoracic Oncology of West China Hospital, Sichuan University, and Zhao Ailin from the Department of Hematology at West China Hospital, Sichuan University, published an article titled "Dual blockade immunotherapy targeting PD-1/PD-L1 and CTLA-4 in lung cancer" in J Hematol Oncol. This article targets the role of dual blockade immunotherapy targeting PD-1/PD-L1 and CTLA-4 in the treatment of lung cancer and further elucidates its preclinical mechanisms and current progress in clinical trials. In addition, the article provides new insights into the potential combination of dual blockade therapy with other strategies to optimize future lung cancer treatment models.
PD-1 and CTLA-4 in tumor immunity
CTLA-4 is expressed at high levels during the initial activation phase of T cells. CTLA-4 competes with CD28 for binding to B7 (also known as CD80 and CD86) on APCs, sending inhibitory signals to T cells. CTLA-4 inhibitors can restore immune activity by targeting CTLA-4.
In the later stages of the immune response, PD-1 is expressed on activated T cells, where it inhibits T cell receptor-mediated effector functions through its ligands PD-L1 and PD-L2. PD-1/PD-L1 inhibitors block the PD-1/PD-L1 interaction, thereby exerting anti-tumor effects.
A major challenge in cancer immunotherapy is resistance to ICI therapy, and the mechanisms of ICI resistance can be categorized as tumor-intrinsic and tumor-extrinsic. Tregs, through suppressive cytokines and direct contact, inhibit effector T cell (Teff) function, thereby limiting inflammation and promoting self-tolerance. Tregs have been observed to infiltrate many tumor types, suggesting the presence of an immunosuppressive environment that may contribute to immunotherapy resistance due to an inability to increase or decrease Teffs.
Mechanisms of dual immune checkpoint inhibitor combination therapy
PD-1/PD-L1 and CTLA-4 significantly reduces the proportion of exhausted cytotoxic CD8+ T cells while increasing active effector T cells, including both activated CD8+ and CD4+ effector cells, potentially enhancing immune responses. Combined blockade of PD-1 and CTLA-4 enhances the infiltration of Teffs, resulting in a highly favorable ratio of Teffs to Tregs within tumors. Studies have shown that the emergence of dual blockade therapy can effectively overcome immune tolerance and help reshape immune memory, thereby promoting long-term immune responses.
Mechanism of bispecific antibodies
Bispecific antibodies can target multiple immune checkpoints to alleviate immunosuppressive phenotypes and effectively bypass immune tolerance in the TME. bsAbs targeting co-stimulatory molecules can enhance T cell-mediated immune responses. Furthermore, bsAbs offer the unique advantage of cross-linking two cell types or binding two molecules in cis on the cell membrane. By modulating the affinity of the two binding sites, bsAbs help minimize off-target effects in normal tissues and contribute to the reduction of treatment-related adverse events (TRAEs). This therapeutic approach improves the specificity of cancer treatment.
Current status of dual immune checkpoint inhibitor combination therapy
Dual immunotherapy combining PD-1/PD-L1 and CTLA-4 inhibitors has been approved for a variety of cancer indications, such as the nivolumab + ipilimumab regimen, a combination of PD-1 and CTLA-4 inhibitors. These inhibitors are widely used in the treatment of various tumor types, including melanoma, renal cell carcinoma, colorectal cancer, hepatocellular carcinoma, mesothelioma, and esophageal squamous cell carcinoma.
Nivolumab combined with ipilimumab
The Phase I trial CheckMate012 (NCT01454102), the Phase II trial CheckMate568, and the Phase III trial CheckMate227 evaluated the efficacy and safety of dual ICI combination therapy in patients with advanced NSCLC. Combination therapy improved safety and better clinical outcomes. TMB was also highlighted as a potential predictive biomarker for the efficacy of ICI combination therapy. Beyond NSCLC, numerous clinical trials are evaluating the efficacy and application of nivolumab and ipilimumab combination therapy as dual immunotherapy in SCLC, demonstrating its efficacy and safety in this setting.
Durvalumab combined with tremelimumab treatment
In a phase III study, MYSTIC, the efficacy of durvalumab combined with tremelimumab therapy in previously untreated advanced NSCLC was evaluated. In subgroup analysis, it was found that patients with a single bTMB ≥ 20mut/Mb had significantly improved OS in dual ICI combination therapy compared with single drug and chemotherapy.
Safety and limitations of dual ICI combination therapy
Compared with ICI monotherapy and chemotherapy, dual ICI combination therapy significantly improves efficacy, mitigates secondary drug resistance, prolongs remission time, and provides significant survival benefits. However, it also carries an increased risk of TRAEs, and the opportunities for combination therapy with other drugs and treatment modalities (chemotherapy, radiotherapy, targeted therapy) are quite limited, which may further increase the risk of TRAEs.
Bispecific antibodies
Bispecific antibodies (BsAbs) can not only enhance the efficacy of immunotherapy but also reduce treatment-related toxicities. PD-1/PD-L1 and CTLA-4 are the most established targets in ICI. In addition, there are many other popular targets that play an important role in the treatment and development of lung cancer, such as DLL3, ICOS, LAG-3, and TIGIT.
BsAb targeting PD-1×CTLA-4
Cadonilimab (AK104) is a humanized bsAb targeting PD-1 and CTLA-4. As a symmetrical tetravalent bifunctional antibody, it binds simultaneously with high affinity to PD-1 and CTLA-4 expressed on tumor-infiltrating lymphocytes (TILs), achieving a co-targeting effect, enhancing anti-tumor efficacy while improving safety. The COMPASSION-01 (NCT03261011) clinical trial demonstrated promising efficacy and remarkable tolerability in patients with advanced solid tumors.
QL1706 (PSB205) is a bifunctional bsAb comprising an engineered monoclonal antibody, anti-PD-1 IgG4, and anti-CTLA-4 IgG1. Furthermore, a novel MabPair technology platform is employed, enabling the production of two antibodies that closely resemble their native forms from a single host cell and into a single product. In QL1706, each antibody has been individually optimized, with the anti-CTLA-4 antibody having a shorter elimination half-life (t1/2) to minimize exposure and reduce the risk of irAEs.
BsAb targeting PD-L1×CTLA-4
KN046 is a novel bsAb targeting PD-L1 and CTLA-4, inhibiting the interactions between PD-L1 and PD-1, and between CTLA-4 and CD80/CD86. KN046 can mediate the depletion of regulatory T cells in the TME, thereby enhancing anti-tumor immune responses and alleviating immunosuppression.
BsAbs against other antigens
CTX-8371, developed by Compass Biosciences, is a bsAb targeting PD-1 and PD-L1. It has a 2+2 symmetrical structure and utilizes common light chain technology. It converts PD-1-positive cells into PD-1-negative cells through multiple pathways, thereby enhancing anti-tumor efficacy.
AK112 is a humanized IgG1bsAb targeting PD-1 and VEGF. AK112 combined with platinum-based double therapy has shown good anti-tumor activity and safety and can be used as a first-line treatment for patients with advanced NSCLC. This regimen was approved for marketing in 2015.
Amivantamab is a bsAb targeting EGFR and MET. It has received accelerated approval from the US FDA for the second-line treatment of NSCLC with exon 20 insertions, becoming the world's first targeted therapy for this mutation.
Tarlatamab, a bsAb targeting delta-like ligand 3 (DLL3) and CD3, is being evaluated for the treatment of SCLC and has been found to have a favorable safety profile. The FDA granted tarlatamab rapid approval on May 16, 2024, as an innovative therapy for ES-SCLC.
Combination strategies of dual ICIs and bsAbs
Combination chemotherapy: Chemotherapy remains one of the main first-line treatments for NSCLC and small cell lung cancer. During cancer treatment, chemotherapy drugs exert a bidirectional effect on the immune system, causing systemic immunosuppression while also eliminating specific immune cells and helping to rebuild the immune system. In a Phase III clinical study (CheckMate 9LA) of nivolumab and ipilimumab combined with chemotherapy, the combination therapy prolonged survival compared to chemotherapy alone. Combining chemotherapy and immunotherapy is a promising treatment strategy.
Combined with radiotherapy: Radiotherapy can trigger local and systemic immune responses through various mechanisms, thereby exerting multifaceted effects on tumor immunity. For example, it can promote the maturation of dendritic cells (DCs) and initiate specific immune responses. Immunotherapy can enhance abscopal effects, while radiotherapy can amplify the efficacy of immunotherapy. A randomized phase II study investigating recurrent SCLC combined durvalumab and tremelimumab with radiotherapy (SBRT) found that dual ICI combined with radiotherapy prolonged survival.
Combined targeted therapy: Studies have shown that targeted cancer therapies can trigger ICD in tumor cells, thereby enhancing the efficacy of ICIs. This discovery makes it possible to combine targeted cancer therapy with immunotherapy, providing a new approach to overcome drug resistance and improve clinical efficacy. A Phase III clinical trial, IMspire150 (NCT02908672), found that combined targeted therapy with immunotherapy prolonged PES.
Combined with other therapies: Combining ICIs with CAR-T cells can enhance the clinical efficacy of CAR-T cell therapy. Furthermore, CAR-NK cell therapy and macrophage-targeted therapy also have the potential to be combined with immunotherapy, providing more options and possibilities for cancer treatment.
Summarize
Dual ICI immunotherapy can enhance tumor efficacy, but carries the risk of TRAEs. The introduction of bsAbs addresses this challenge, achieving a balance between efficacy and safety. However, both dual ICI combination therapy and bsAbs have their limitations. The emergence of combined chemotherapy, radiotherapy, and targeted therapy offers new possibilities. With the continuous advancement of science and technology, these therapies will continue to be optimized and developed, heralding a new era in cancer immunotherapy.
