Immunotherapy refers to a treatment strategy that involves inducing, enhancing, or suppressing immune responses to manage diseases. At present, most immunotherapeutic approaches remain under exploration.
Foundations of Immunotherapy for Gynecological Tumors
There are complex interactions between tumor cells, the host immune system, and the surrounding environmental components. The immune system has the capacity to recognize, destroy, and eliminate tumor cells, while tumor cells can evade immune system detection and destruction through various mechanisms, a process known as immune escape. The state of immune responses in tumor patients is often correlated with their disease prognosis. Enhanced immune responses in early cervical cancer or precancerous lesions have shown the ability to suppress tumor progression. However, the immune system can also play a role in tumor development and progression. For instance, tumor-associated macrophages can promote tumor angiogenesis.
Under physiological conditions, the immune system identifies tumor cells and generates innate or adaptive immune responses, activating and differentiating relevant effector cells that release molecules to kill and eliminate tumor cells. This understanding lays the foundation for developing immunotherapies targeting various aspects of immune responses.
Tumor antigens, which arise during cellular transformation processes, include tumor-specific antigens and tumor-associated antigens. These antigens provide robust immunotherapeutic targets. In gynecological oncology, tumor antigens include HPV-specific antigens (e.g., E6/E7 oncoproteins) in cervical cancer and tumor-associated antigens such as NY-ESO-1, mesothelin, and cancer antigen 125 (CA125), which are overexpressed in various cancers.
Patients commonly undergo biomarker testing for PD-L1, MSI/MMR, and TMB before immunotherapy. Tumors characterized by PD-L1 upregulation, mismatch repair deficiency (dMMR), microsatellite instability-high (MSI-H), or high tumor mutation burden (TMB-H) belong to a population more likely to benefit from immunotherapy. Among these, MSI-H/dMMR and TMB-H tumors are genetically unstable and have a higher likelihood of expressing neoantigens, which elicit specific immune responses and better therapeutic outcomes. PD-L1 is expressed in cervical cancer, endometrial cancer, ovarian cancer, and drug-resistant trophoblastic tumors, while MSI-H/dMMR and TMB-H profiles are also found in cervical, endometrial, and ovarian cancers. In addition, hypermutated POLE (DNA polymerase epsilon) tumors in endometrial cancer are characterized by genetic instability and high neoantigen expression, making them beneficial candidates for immunotherapy.
Immunotherapy Strategies for Gynecological Tumors
Immunotherapy strategies for gynecological tumors can be categorized into three types: immune modulation therapies, passive immunotherapies, and active immunotherapies. Immune modulation therapies include the use of immune checkpoint inhibitors and cytokine-based treatments. Passive immunotherapies encompass antibody-based targeted therapies, which directly attack tumor cells, and adoptive cell therapies. Active immunotherapies involve tumor vaccines and innate immune system activators.
Immune Modulation Therapies
Immune checkpoint inhibitor (ICI) therapies are currently the most widely used immunotherapeutic drugs in clinical practice. Immune checkpoints regulate the degree of immune activation under normal physiological conditions to prevent autoimmunity. However, tumors can exploit these mechanisms to suppress immune responses, effectively applying an "immune brake." ICIs, using monoclonal antibodies, block this immune brake mechanism and restore the immune system's cytotoxic activity.
ICIs are primarily effective in advanced or metastatic solid tumors with MSI-H/dMMR or TMB-H profiles. They have demonstrated promising efficacy in cases of advanced, metastatic, or recurrent cervical and endometrial cancer. ICIs have also been employed to treat drug-resistant trophoblastic tumors. Common immune checkpoint targets include PD-1 and its ligand PD-L1, as well as cytotoxic T-lymphocyte-associated protein 4 (CTLA-4). PD-L1, when overexpressed in tumors, binds to PD-1 on activated effector T cells, suppressing their antitumor activity. CTLA-4, an inhibitory molecule on T cells, blocks the activation of T cells by antigen-presenting cells.
Emerging immune checkpoint molecules, including lymphocyte activation gene 3 (LAG-3), T cell immunoreceptor with immunoglobulin and ITIM domains (TIGIT), T cell immunoglobulin and mucin domain-containing protein 3 (TIM-3), and V-domain immunoglobulin suppressor of T cell activation (VISTA), and their related therapies show potential for clinical application. LAG-3 inhibitors, for instance, have already been approved for the treatment of melanoma.
Immune modulation therapies also involve the administration of immunomodulatory agents such as interleukins, tumor necrosis factor, macrophage colony-stimulating factor, and interferons. However, due to limited systemic responsiveness and substantial toxic side effects, these approaches have not yet entered clinical practice.
Passive Immunotherapy
Antibody-Targeted Tumor Therapy
The antibody-antigen complex can bind to macrophages, natural killer cells, or complement through its Fc region, leading to antibody-dependent cell-mediated cytotoxicity (ADCC) or phagocytosis, as well as complement cascade reactions that destroy tumors. Antibodies can also block tumor-specific growth factor receptors, thereby inhibiting signaling pathways related to tumor growth, invasion, and metastasis.
In gynecological oncology, antibodies targeting HER2 and EGFR have been employed. Additionally, therapies targeting CA125 for ovarian cancer treatment are under development.
Adoptive Cell Therapy (ACT)
Adoptive cell therapy refers to the infusion of immune cells with antitumor activity into patients. ACT involves tumor-infiltrating lymphocytes (TILs) harvested, expanded, and re-infused into patients, as well as engineered cells carrying receptors specific to tumor antigens.
Chimeric antigen receptor (CAR)-T cells have been successfully applied in the treatment of hematological malignancies, and their use in gynecological tumors is being explored. For example, CAR-T therapies targeting mesothelin are under investigation for ovarian cancer and cervical cancer. However, CAR-T therapy faces challenges such as cytokine release syndrome, neurotoxicity, antigen escape, and limited durability of therapeutic effects. Furthermore, CAR-T cells can only recognize antigens on the tumor cell surface, which limits their ability to penetrate the tumor microenvironment, leading to suboptimal results in solid tumors, including gynecological cancers.
T-cell receptor (TCR)-engineered T cells represent a new ACT option for treating advanced cancers. TCR-T therapy involves introducing TCRs capable of recognizing tumor antigens into effector T cells, which then specifically target and kill tumor cells expressing the target antigens upon infusion into the patient. This highly specific cellular therapy holds promise for minimizing damage to normal cells while enhancing both efficacy and safety. In cervical cancer, TCR-T therapies targeting HPV E6/E7 antigens have shown initial efficacy. Meanwhile, TCR-T therapies targeting "universal" tumor antigens such as p53, EGFR, and KRAS are being investigated. However, the clinical application of such therapies requires further research and validation.
Active Immunotherapy
Tumor Vaccines
Tumor vaccines are divided into prophylactic and therapeutic vaccines. HPV vaccines are a successful application of prophylactic vaccination for preventing cervical cancer. The principle involves using recombinant technology to incorporate viral surface antigenic epitopes into virus-like particles (VLPs), which are similar in size and structure to HPV but lack infectivity. This approach ensures both immunogenicity and safety.
VLPs induce humoral immune responses, generating high-titer specific antibodies and memory B cells. By doing so, the immune system eliminates infected cells with HPV-specific antigens at the early stage of infection, thereby preventing long-term infection and reducing the incidence of cervical cancer. However, these vaccines are ineffective in individuals already infected with HPV.
Therapeutic vaccines aim to activate the immune system using tumor-associated antigens, with the goal of killing tumor cells, eradicating residual microscopic disease, and establishing durable antitumor immunity. These vaccines include protein (peptide) vaccines, genetic vaccines (e.g., DNA or RNA vaccines encoding antigen peptides), and cell-based vaccines (loaded with antigens or genetic material).
Dendritic cells (DCs), specialized antigen-presenting cells that activate naïve T cells, have been loaded with HPV E2 and E6/E7 protein antigens to develop DC and bacterial vaccines. These vaccines have shown preliminary efficacy in clinical trials for treating HPV-associated cervical intraepithelial neoplasia. Additionally, studies indicate that vaccinating post-treatment can reduce recurrence rates of high-grade cervical intraepithelial lesions.
NY-ESO-1, expressed in approximately 43% of ovarian cancer cases, has been targeted in clinical trials of NY-ESO-1 ovarian cancer vaccines, yielding some efficacy. The oncogene WT1, highly expressed across various gynecological cancers, also makes WT1 peptide vaccines a potential therapeutic option.
Innate Immune Activators
Innate immune activators include Toll-like receptor (TLR) agonists, oncolytic viruses, and Listeria-based treatments. Oncolytic viruses and Listeria can also serve as carriers for tumor vaccines or targeted therapies.
Oncolytic viruses are tumor-killing viruses capable of infecting and replicating within tumor cells, simultaneously destroying tumor cells and eliciting antitumor immune responses. GL-ONC1, an oncolytic modified vaccinia virus strain, has reached Phase III clinical trials for evaluating its efficacy in combination with chemotherapy and VEGF inhibitors for platinum-resistant/refractory ovarian cancer.
Oncolytic adenoviruses such as KD01 are being assessed in clinical settings for the treatment of cervical, endometrial, vulvar, and ovarian cancers, in combination with radiotherapy, chemotherapy, or immune checkpoint inhibitors.
Immunotherapy for Gynecological Tumors in Clinical Application
The immunotherapy drugs for gynecological tumors currently approved for clinical use are predominantly immune checkpoint inhibitors (ICIs), including PD-1/PD-L1 antibodies and PD-1/CTLA-4 bispecific monoclonal antibodies. ICIs can be combined with chemotherapy, anti-angiogenic agents, and PARP inhibitors to enhance therapeutic efficacy.
Immunotherapy for Ovarian Cancer
Patients should undergo testing for MSI, MMR, and TMB to evaluate their potential benefit from immunotherapy. For platinum-resistant recurrent ovarian cancer patients with MSI-H/dMMR or TMB-H status, treatment with PD-1 antibodies is an option. Ovarian cancer is considered an "immunotherapy cold tumor," as its microenvironment lacks the immune cells necessary for mobilization, which limits the overall effectiveness of immunotherapy.
Immunotherapy for Endometrial Cancer
Following previous systemic therapies and biomarker evaluations (MMR, MSI, TMB), PD-1 antibodies may be used in later-line treatments or even in first-line therapy for recurrent cases. In late-line treatment, PD-1 antibodies are suitable for advanced or recurrent endometrial cancer patients with MSI-H/dMMR or TMB-H who have experienced treatment failure. For patients with mismatch repair proficiency (pMMR), PD-1 antibodies combined with the multikinase inhibitor lenvatinib have shown efficacy.
Recent studies have demonstrated that in first-line treatment for advanced or recurrent endometrial cancer, combining PD-1 antibodies with chemotherapy significantly improves survival regardless of biomarker status.
Immunotherapy for Cervical Cancer
In patients with recurrent or metastatic cervical squamous cell carcinoma, adenocarcinoma, or adenosquamous carcinoma, PD-1 antibodies have shown some efficacy in later-line treatment for PD-L1-positive patients after the failure of platinum-based therapies. Furthermore, in first-line treatment for advanced, metastatic, or recurrent cases, the addition of immunotherapy (such as pembrolizumab) to platinum-based chemotherapy with or without bevacizumab has provided significant clinical benefits.
PD-1/CTLA-4 bispecific monoclonal antibodies have also demonstrated benefits for patients with recurrent or metastatic cervical cancer who have failed prior platinum-based therapies.
Immunotherapy for Other Gynecological Tumors
PD-L1 is widely expressed in gestational trophoblastic tumors, and certain PD-1 antibodies may be considered for high-risk, drug-resistant cases. In vulvar or vaginal cancers expressing PD-L1 positivity, TMB-H, or MSI-H/dMMR status, treatment with PD-1 antibodies can be considered. For patients with unresectable or metastatic vulvar or vaginal melanoma, therapy with CTLA-4 antibodies and/or PD-1 antibodies may be a therapeutic option.
Summary and Outlook
Targeted therapy and immunotherapy have emerged as the most significant novel therapeutic modalities following surgical treatment, chemotherapy, and radiotherapy. The use of anti-angiogenic agents in combination with chemotherapy has significantly improved outcomes in gynecological malignancies. PARP inhibitor maintenance therapy has transformed the treatment landscape for ovarian cancer, markedly extending patient survival. Immune checkpoint inhibitors have shown notable efficacy in both later-line and first-line therapies for advanced, recurrent, or metastatic cervical and endometrial cancers. Antibody-drug conjugates have demonstrated encouraging prospects in the treatment of cervical and ovarian cancers.
Precision therapy is underpinned by precision diagnostics. Molecular detection methods such as next-generation sequencing facilitate clinical molecular diagnostics. Specific molecular testing or comprehensive molecular profiling aids in accurately determining prognosis and guiding treatment strategies.
A wide range of targeted and immunotherapeutic drugs have the potential to become principal agents in the treatment of gynecological cancers. Antibody-drug conjugates may replace many nonspecific cytotoxic drugs and serve as the primary targeted chemotherapeutic agents for gynecological tumors. Numerous clinical trials are underway both domestically and globally to explore more precise and effective modalities for targeted and immunotherapy in gynecological cancers.
It is recommended that eligible gynecological cancer patients, particularly those with refractory, recurrent, or metastatic disease, actively participate in high-quality clinical trials.