Cervical cancer is the third most common malignant tumor in women worldwide in terms of both incidence and mortality. The field of cervical cancer treatment is rapidly evolving, and various combination therapies are being explored to enhance the efficacy of immune checkpoint inhibitors (ICI) and provide new treatment options for patients at different disease stages. Clinical trials involving immune checkpoint inhibitors are now being conducted following a phase 3 trial with cemiplimab, an ICI, which demonstrated a significant improvement in prognosis in advanced or metastatic cervical cancer patients. These trials include monotherapy and combination therapy with other immune therapies, chemotherapy, or radiation therapy. Furthermore, other approaches for controlling tumors via the immune system, such as therapeutic vaccination for specific tumor antigens or immune cell therapy including chimeric antigen receptor (CAR)-T cell therapy and tumor-infiltrating lymphocytes are being investigated. Ongoing trials will continue to illuminate the optimal strategies for combining these therapies and addressing challenges associated with immune checkpoint failure in cervical cancer. Herein, we conducted a review of articles related to immunotherapy for cervical cancer and describe current treatment strategies for cervical cancer via immunotherapy.
Hinweise
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Introduction
Cervical cancer is the third most prevalent malignant tumor among women globally both in terms of incidence and mortality [1]. Particularly challenging are recurrent or advanced cases that are unresponsive to primary treatments and thus have a bleak prognosis. The introduction of the human papilloma virus (HPV) vaccine on a global scale has demonstrated effectiveness in preventing HPV-related neoplasms [2]. However, regional disparities in vaccine adoption persist, and cervical cancer remains a substantial concern not only in countries where the HPV vaccine is not widely available but also in countries where the vaccine is commonly administered. For example, in the United States, survival rates have shown minimal improvement since the 1970s, and instances of stage IV advanced cervical cancer are increasing [3].
Consequently, novel treatment approaches are urgently required. Although conventional cytotoxic chemotherapy has yielded limited improvements in prognosis, reports on the efficacy of immunotherapy for cervical cancer are increasing. Cervical cancer is often associated with persistent HPV infection, and the HPV oncoproteins E6 and E7 expressed in tumor cells, play a pivotal role in tumorigenesis and the maintenance of malignant characteristics; therefore, these oncoproteins are considered ideal targets for the immune system [4]. This underscores the potential of targeting HPV via immunotherapies, such as antibodies and therapeutical vaccines, and HPV-related cancers via T-cell therapies. Numerous encouraging prospects exist for harnessing the immune system in treating cervical cancer [5]. This review aims to explore recent advances and evidence in immunotherapy, including the use of immune checkpoint inhibitors (ICIs), various immune-related therapies, and combination therapies for cervical cancer.
Tumor microenvironment in cervical cancer
HPV is a small double-stranded DNA virus that is the major cause of cervical cancer [6]. Following the initial HPV infection, the viral DNA can integrate into the host genome [7] and this integration is linked to the progression from intraepithelial neoplasia to invasive carcinoma [8]. The E6 and E7 HPV oncoproteins promote cell proliferation and immortalization by inactivating cancer suppressor genes p53 and Rb [9]. In Cervical cancer tumor microenvironment complex interaction of immune cells that contribute to both tumor progression and immune evasion. CD8+ T cells play a key role in attacking tumor cells. They are stimulated by cytokines such as IL-2, which promotes their differentiation into cytotoxic T lymphocytes (CTLs), enhancing their ability to target and eliminate cancer cells. The cytotoxic activity of CTLs is mediated through molecules such as perforins and granzymes. Another important T cell population is CD4+ T cells, which help create an anti-tumor microenvironment by secreting inflammatory cytokines like IL-2. In contrast, regulatory T cells induced by immunosuppressive cytokines such as TGF-beta and IL-10, suppress immune response and contribute to immune evasion. Additionally, dendritic cells play a role in antigen presentation and the activation of immune cells. Tumor-associated macrophages, especially M2 macrophages, promote tumor cell growth and immune suppression [10]. Despite the detection of HPV-specific cytotoxic T-lymphocytes in tumors [11], the immune system often fails to eliminate the tumor, indicating that an immunosuppressive environment is present in cervical cancer [6]. This means that HPV shapes the microenvironment to mediate persistent infections that favor transformation and tumor development [10]. The antigens are recognized by T cells, and this recognition is controlled by costimulatory and inhibitory molecules. The cervical cancer cells overexpress an immune checkpoint molecule, PD-L1, which binds to the T cell immune checkpoint molecule PD-1 to suppress T cell activation. In addition, oncoproteins E6, E7 induce CTLA-4 expression and suppress T cell functions, thereby inducing an antitumor immune response. A key mechanism is the immune checkpoint pathway including PD-1, CTLA-4, and PD-L1, which increase immune resistance [12] (Fig. 1).
Fig. 1
Co-stimulatory and inhibitory molecules regulate T cell activation and immune responses. Co-stimulatory molecules (e.g., CD28) promote T cell activation, proliferation, and cytokine production, whereas inhibitory molecules (e.g., CTLA-4, PD-1) suppress these processes
×
Immune checkpoint antibodies in cervical cancer
The landscape of immune-checkpoint antibodies used in clinical trials for cervical cancer continues to expand. Representative agents include anti-PD-1 antibodies (pembrolizumab, cemiplimab, nivolumab, and balstilimab), anti-PD-L1 antibodies (durvalumab, atezolizumab), and anti-CTLA-4 antibodies (ipilimumab). These agents function by blocking checkpoint molecules, thereby reactivating the immune response against cancer cells.
Immune checkpoint inhibitor monotherapy
Advanced and/or metastatic cervical cancer
Paclitaxel and platinum-based chemotherapy are now standard treatments for metastatic and recurrent cervical cancer [13]. In the GOG 240 trial, the addition of the anti-vascular endothelial growth factor (VEGF) antibody, bevacizumab, to chemotherapy increased survival [14]. However, the results revealed that options remained limited in term of second-line regimen for these patients; selected trials for patients with metastatic or recurrent cervical cancer are listed in Table 1. The KEYNOTE-028 trial (NCT02054806) [15] and KEYNOTE-158 trial (NCT02628067) [16] demonstrated the efficacy and the safety of pembrolizumab. The results of these trials led to FDA approval of pembrolizumab for cervical cancer with PD-L1 expressed tumors. The efficacy of monotherapy with nivolumab, another anti-PD-1 inhibitor for cervical cancer was investigated with NRG-GY002 (NCT02257528) [17] and CheckMate 358 trial (NCT02488759) [18].
Table 1
Selected trials for patients with metastatic or recurrent Cervical cancer
Recurrent/metastatic HPV16 cervical cancer after first line chemotherapy
–
100
–
16.8
3.0
13.3
P phase, CCRT concurrent chemoradiation, M months, Rec/Meta recurrent/metastatic, ORR objective response rate, PFS progression free survival, OS overall survival, NS statistically not significant, Q quaque, IV intravenously, RT Radiotherapy, MTD maximum tolerated dose, PST prior systemic therapies, CR complete response
aASCO meeting
bIncluding 17 cervical cancer patients
In contrast to the KEYNOTE-158 trial where pembrolizumab exclusively demonstrated responses in PD-L1-positive patients. A phase II study with the anti-PD-1 inhibitor balstilimab (NCT03104699) [21] showed efficacy in patients with PD-L1 negativity. Ipilimumab, a fully humanized monoclonal antibody targeting CTLA-4 that downregulates the T cell immune response, was investigated in a phase I/II study. Although ipilimumab was tolerable, this did not show significant single-agent activity [19]. The first phase III trial demonstrating beneficial overall survival (OS) of a checkpoint inhibitor in cervical cancer was EMPOWER-CERVICAL-1 (NCT03257267). This trial, involving the anti-PD-1 inhibitor cemiplimab as the second-line treatment [32] and enrolled patients who had progressed after platinum-containing therapy. Although median progression-free survival (PFS) was similar in both treatment groups (2.8 months for cemiplimab vs. 2.9 months for chemotherapy), the hazard ratio of 0.71 (95% CI 0.58–0.86; P < 0.001) indicated a significantly longer PFS conferred by cemiplimab than by chemotherapy. Notably, in this trial, patients with PD-L1 Combined Positive Score (CPS) < 1% demonstrated an objective response to cemiplimab, suggesting a potential effectiveness for PD-L1-negative patients [32]. The mechanism is not clear; however, immune cells within the tumor microenvironment are often suppressed by the PD-1 checkpoint molecule. Anti-PD-1 inhibitors may overcome this suppression, reactivating immune cells to exert anti-tumor effects. These trials demonstrated that monotherapy with anti-PD-1 drugs, such as cemiplimab, is effective for patients with recurrent cervical cancer including PD-L1-negative patients.
Combination therapy
In combination therapy, the release of damage-associated molecular patterns (DAMPs) [33] from cells under the influence of coadministered cytotoxic drugs may potentially enhance the efficacy of ICIs by influencing the immune environment. A phase II trial combining atezolizumab with bevacizumab did not indicate efficacy when used as the second-line treatment for patients with cervical cancer who had previously received bevacizumab in chemotherapy [22]. The history of treatment with bevacizumab may influence the results.
Combination immunotherapy
Although monotherapy with ipilumumab, an anti-CTLA-4 inhibitor, did not demonstrate significant activity in cervical cancer, combination therapy with anti-PD-1 antibodies has shown potential effectiveness. The CheckMate 358 trial, a phase I/II multicohort trial with nivolumab and ipilumumab, demonstrated notable efficacy in patients treated with nivolumab and ipilumumab followed by that in patients who had undergone systemic therapies and were subsequently treated with nivolumab [20]. Another immune checkpoint doublet trial, with the anti-PD-1 inhibitor balstilimab and anti-CTLA-4 inhibitor zalifrelimab, also showed a high objective response rate (ORR) [26]. In combination therapy using an anti-T cell immunoreceptor with Ig and ITIM domains (TIGIT) inhibitor, tiragolumab and an anti-PD-L1 inhibitor, atezolizumab, the response rate was higher than with atezolizumab alone, although this did not reach statistical significance (SKYSCRAPER-04, NCT04300647) [34]. The combined treatment of pemblrolizumab, with another TIGIT inhibitor, vibostolimab, did not produce improvement in prognosis compared with pembrolizumab alone (KEYVIBE-005, NCT50007106) [35]. Other combinations, including the anti-GITR inhibitor (INCAGNO1876) with nivolumab, and/or ipilimumab, are currently being investigated (NCT03126110) [27]. Those trials indicate that combination immunotherapy may be a promising approach, although the selection of patients for the demonstration of efficacy requires further discussion.
Combination immunotherapy with chemotherapy
For a first-line treatment for advanced/metastatic cervical cancer, a phase III trial, KEYNOTE-826 trial (NCT03635567) demonstrated that combining immune checkpoint therapy using the anti-PD-1 inhibitor pembrolizumab with chemotherapy improved the prognosis. Bevacizumab was used in > 60% of patients in both arms of the trial (hazard ratio, 0.65; 95% CI 0.53–0.79; P < 0.001) [24]. The combination of chemotherapy with pembrolizumab showed improved survival with tolerable side effects, leading to FDA approval for the ICI combination treatment for patients with advanced/metastatic cervical cancer. Another notable phase III trial that assessed first-line combination therapy for metastatic or recurrent cervical cancer is BEATcc (NCT03556839), which indicated a benefit of adding atezolizumab, anti-PD-L1 inhibitor, to the GOG-240 trial regimen (chemotherapy with bevacizumab) [14] in patients with metastatic/recurrent cervical cancer [25]. The anti-VEGF antibody bevacizumab interferes with the composition and function of several immune cells within the tumor microenvironment, including T cells [36]. In a phase II trial conducted as a second-line treatment, no therapeutic effect was observed with the use of atezolizumab with bevacizumab [22]. The previous treatment history of patients with bevacizumab may have influenced the outcome. The BEATcc trial showed that the combination of bevacizumab and ICI may more effectively modulate the tumor microenvironment.
Another approach involves using combinations with drugs targeting checkpoints beyond PD-1, PD-L1, CTLA-4, or TIGIT. Co-stimulation molecules, including LAG-3, VISTA, ICOS, and OX40, serve as targets for combination drugs in patients with cervical cancer [37] (NCT05864144, NCT03829501). Selected trials for ongoing trials for patients with cervical cancer are listed in Table 2.
Table 2
Selected on-going trials for patients with cervical cancer
P phase, M months, ORR overall response rate, PFS progression free survival, OS overall survival, Q quaque, Rec/Meta recurrent/metastatic, RT radiation therapy, SCC squamous-cell carcinoma, CCRT concurrent chemoradiotherapy, TEAE Number of patient reporting treatment-emergent adverse events, BID twice daily, NSCLC non-small cell lung cancer, HNSCC head and neck squamous cell carcinoma, HCC hepatocellular carcinoma, TC paclitaxel + carboplatin
*ESMO (European Society for Medical Oncology) congress
Combination with targeted therapy
Targeting therapies have demonstrated a degree of effectiveness for cancer, and a synergistic effect is expected in combination with ICIs. For example, one approach involves combining ICIs with anti-angiogenic agents like bevacizumab. Tumor angiogenesis not only promotes tumor growth and metastasis but also creates an immunosuppressive microenvironment by reducing T-cell infiltration and increasing regulatory T cells and myeloid-derived suppressor cells (MDSCs). Anti-angiogenic therapy normalizes the tumor vasculature, facilitating T cell infiltration and enhancing the efficacy of ICIs [38]. The PD-1 inhibitor camrelizumab (SHR-1210) is efficacious in combination with chemotherapy as a first-line treatment and demonstrated a tolerable response with the tyrosine kinase inhibitor apatinib as a second-line treatment [23, 29]. Combining ICIs with PARP inhibitors is being explored for patients with recurrent cervical cancer [39], (GOTIC-025/NCT04641728). For uterine endometrial cancer, the combination of lenvatinib, which helps reduce tumor-associated macrophages (TAMs) and activate CD8+ T cells and pembrolizumab increased the prognosis [40, 41], potentially overcoming VEGF-mediated immunosuppression. The combination has also been investigated in patients with advanced cervical cancer (NCT04865887). A phase 1/2 trial for pembrolizumab with the NETrin monoclonal antibody that can inhibit tumor growth in endometrial cancer [42] are being investigated in patients with gynecologic cancer (GYNET/NCT04652076). Another strategy leverages targeted agents that modulate specific signaling pathways, such as inhibitors of VEGF, EGFR, or PI3K/AKT/mTOR. mTOR pathway inhibitors have been shown to reduce regulatory T cell activity and promote cytotoxic T cell responses. These effects may synergize with ICIs to improve anti-tumor immune activity [43]. mTORC1/2 inhibitor, onatasertib, and anti-PD-1 inhibitor, toripalimab demonstrated encouraging an ORR of 53.3% in 31 patients with cervical cancer (NCT04337463) [44].
Immunotherapy for locally advanced cervical cancer
Concurrent chemoradiotherapy (CCRT) is used as the standard treatment for locally advanced cervical cancer (LACC). CCRT with a weekly cisplatin regimen has demonstrated improved survival compared with radiotherapy alone [45, 46]. Notably, radiotherapy can enhance immune responses when combined with PD-1 ICIs in melanoma [47]. This observation prompted the initiation of clinical trials combining ICIs with the standard treatment of CCRT in LACC. Selected trials for patients with LACC are listed in Table 3. The phase I trial, GOG-9929, demonstrated the safety of adjuvant ipilimumab following CCRT [48], and a phase II trial indicated a similar safety profile for adjuvant or maintenance pembrolizumab with CCRT [49]. Additionally, the NRG GY017 study demonstrated the safety of atezolizumab with CCRT for high-risk LACC with lymph node metastasis [50]. Both studies affirmed the safety of adjuvant or concurrent ICIs with CCRT. In phase III trials of ICIs for treating LACC, the CALLA trial (NCT03830866), is a randomized phase III trial that adds the PD-L1 inhibitor durvalumab to CCRT for 770 patients with LACC. In the durvalumab-adding population (n = 385), the PD-L1 CPS ≥ 1% was 28.7%, and in the placebo-adding population (n = 385), the PD-L1 CPS ≥ 1% was 33.2%. In the intention-to-treat population, PFS did not significantly differ between the durvalumab plus CCRT group and the placebo plus CCRT group (HR 0.84; 95% CI 0.65–1.08; P = 0.17) [51]. The inclusion of para-aortic lymph node-positive patients and other factors may have influenced the results. In another trial, the ENGOT-cx11/GOG-3047/KEYNOTE-A18 study (NCT04221945) involving 1060 patients, pembrolizumab combined with CCRT (n = 529) demonstrated a significant improvement in PFS compared with that in the placebo combined with CCRT group (n = 531), with a 24-month PFS of 67.8% vs 57.3%, respectively (P = 0.0020) [52]. The differences in the results between CALLA trial and KEYNOTE-A18 may be influenced by several factors, KEYNOTE-A18 trial targeted a higher risk population, including criteria such as lymph node size or number, and also differed in sample size and ICIs. The finding from the KEYNOTE-A18 supported the FDA approval of pembrolizumab plus chemoradiotherapy in high-risk cervical cancer. Although the use of ICIs for LACC present a favorable treatment option, the appropriate timing to initiate ICIs and the biomarker for response remain unclear. In the phase I NiCOL trial (NCT03298893), which included 16 patients with LACC, the safety and tolerance of nivolumab with and following CCRT were investigated [53]. The results indicated that nivolumab with and following CCRT is tolerable, with an ORR of 93.8%. Patients with progression-free status demonstrated an active stromal immune infiltrate, and tumor-infiltrating CD3+ T cells were found in closer proximity to PD-L1+ tumor cells than in patients with progressive disease. This suggests a specific tumor microenvironment is related to the response to the treatment of CCRT and ICIs in LACC. Additionally, the induction chemotherapy before CCRT improved survival compared with CCRT alone in LACC (INTERLACE trial) [54].
Table 3
Selected trials for patients with locally advanced cervical cancer
Camrelizumab (anti-PD-1) + chemotherapy- > surgery or CCRT
ORR
85
FIGO 2018 stage IB3,IIA2, IIB/IIIC1r
42 (CPS ≥ 10)
98
–
–
P phase, M months, ORR overall response rate, PFS progression free survival, OS overall survival, CCRT concurrent chemoradiotherapy, Q quaque, PALN para aortic lymph nodes, SCC squamous-cell carcinoma TAP tumour area positivity, DLT dose-limiting toxicities
aESMO (European Society for Medical Oncology) congress 2023
bASCO congress 2023
Neoadjuvant immune therapy for locally advanced cervical cancer
Furthermore, safety and efficacy were demonstrated by neoadjuvant immunotherapy demonstrated for locally advanced mismatch repaired-deficient colon cancer (NCT03026140) [57]. These results led to several trials with induction ICIs before CCRT for LACC. The multicohort phase I study, GOTIC-018 trial, explored nivolumab as induction and coadministration with CCRT, followed by nivolumab maintenance therapy in a cohort of the study [55]. Results showed that the pre- and coadministration of nivolumab is tolerable and exhibits durable efficacy. The COLIBRI trial, a phase II trial, is evaluating the combination of nivolumab and ipilimumab before CCRT and as maintenance for patients with LACC [58]. A trial of neoadjuvant immunotherapy, camrelizuamb, an anti-PD-1 inhibitor, with chemotherapy for LACC has exhibited promising antitumor activity, including 19% complete response [56]. Several ongoing trials are investigating ICIs with CCRT (ATEZOLACC/NCT03612791, NCT05492123), and the timing of implementation and an appropriate immune checkpoint arm, whether using monotherapy or combinations, are currently under evaluation for patients with LACC; the neoadjuvant immune therapy may also be considered for these patients.
Retreatment strategies post-ICI
The rechallenge using ICIs presents a new avenue for addressing the unmet needs of patients who have experienced disease progression after initial treatment with these inhibitors. However, no trial has demonstrated the efficacy of retrying ICIs for patients with cervical cancer. In melanoma and non-small cell lung cancer, several trials have demonstrated the feasibility of ICI rechallenge for patients who progressed after initial treatment (NCT03334617, NCT03526887, NCT02743819) [59‐61]. Notably, a randomized phase II trial for patients with melanoma who failed PD-1 ICI (NCT03033576) demonstrated that the combination of nivolumab with ipilimumab was more favorable than nivolumab monotherapy [62].
For patients with cervical cancer who have not responded to initial ICIs, planned or ongoing clinical trials are investigating potential options. These include a phase II trial of cadonilimab (bispecific anti-PD-1/CTLA-4) (NCT05824494) and a trial of therapeutic vaccine with atezolizumab or placebo (NCT06099418). While the rechallenge of ICIs for these patients may be a viable option, the detection of biomarkers to identify appropriate patients becomes crucial.
These ongoing trials will provide valuable insights into the feasibility and efficacy of ICI rechallenge in cervical cancer, and the identification of biomarkers will contribute to refining patient selection for this approach. Addressing the challenges associated with disease progression after initial treatment with ICIs remains a significant focus in advancing the therapeutic options for patients with cervical cancer.
Further perspectives of immune therapy in cervical cancer
Based on the results of previous clinical trials, ICIs have consistently demonstrated efficacy in treating cervical cancer. However, the current stage reveals that only a partial population of patients is effectively treated, highlighting the urgent need for appropriate biomarkers to identify individuals who are most likely to benefit from specific therapies. PD-L1 is one of the predictive biomarkers for ICI treatments in solid tumors, and could be assessed by immunohistochemical staining. In the KEYNOTE-158 trial, PD-L1-negative patients showed no response to treatment [16]. Moreover, PD-L1 expression differs significantly between adenocarcinoma and squamous cell carcinoma (SCC) (14% vs. 54%) [63].
Tumor mutational burden (TMB), defined as the total number of somatic mutations per coding region of a tumor genome, is another potential predictive biomarker for response to ICIs. In the KEYNOTE-158 analysis, 21% of cervical cancer patients exhibited high TMB status. Across a cohort of 805 patients, including cervical cancer cases, durable tumor responses to pembrolizumab were observed [64].
Additionally, the presence of tumor-infiltrating lymphocytes (TILs) appears to correlate with improved survival. A higher ratio of CD8+ TILs to CD4+ Tregs is associated with better survival rates in cervical cancer (5-year survival rate: 82% vs. 44%) [65]. While these biomarkers show promise for identifying appropriate patient groups for ICI therapy and predicting prognosis, significant challenges remain. Further research, incorporating real-world clinical outcomes, is essential to refine and validate these predictive tools.
The rechallenge of ICIs in cervical cancer remains unclear. Therefore, the next step involves exploring immune checkpoint combination therapy with other ICIs or alternative therapies such as targeting agents, immune therapies (including vaccination), or adoptive cell therapies. Addressing the treatment strategy for patients experiencing immune checkpoint failure represents an unmet need.
Bispecific molecules are also being explored as a novel type of ICIs. A phase I study with the PD-1 and LAG-3 targeting bispecific molecule, tebotelimab, demonstrated efficacy in a small cohort of patients with cervical cancer [28]. Another ongoing trial involves the bispecific agent anti-PD-1/CTLA-4, cadonilimab [66].
Trials with novel types of ICIs targeting mutations with high affinity are ongoing. BCD-100 (prolgolimab), an anti-PD-1 inhibitor that targets the Fc-silencing LALA mutation, has shown significant antitumor activity in melanoma [67]. The FERMATA/ENGOT-cx13 trial is an ongoing phase III trial exploring BCD-100 as a first-line treatment for advanced or recurrent cervical cancer [67]. At this moment, novel type of ICI have demonstrated limited effectiveness as monotherapies. Therefore, these novel types of ICIs are mainly being evaluated in combination with anti-PD-1 or PD-L1 inhibitors, aiming for a synergistic effect [68].
Adoptive cell therapy (tumor-infiltrating lymphocytes and engineered TCR T cell-based therapy, CAR-T)
Adoptive cell transfer treatment using tumor-infiltrating lymphocytes (TILs) would be a favorable therapeutic option for solid tumors. The FDA approved the first TIL therapy for advanced melanoma in 2024. TILs are isolated from the patient’s tumor tissue and stimulated and expanded to large number by interleukin (IL)−2 treatment. IL-2 helps T cell proliferation and activation. TIL therapy can target cancer cells carrying the patient’s specific neoantigens [69]. TIL therapy may adapt to tumor heterogeneity because this contains T cells with multiple T cell receptor clones [70], making this a favorable treatment. Several trials using TIL therapy for cervical cancer have been reported, including one demonstrating that TILs for cervical cancer can target not only neoantigen but also cancer germline antigens. A single infusion of TILs selected for reactivity against HPV E6 and E7 showed tumor regression in patients with metastatic cervical cancer (NCT01585428) [71]. In a phase II study with LN-145, TIL therapy in patients with recurrent cervical cancer after chemotherapy demonstrated therapeutic efficacy with the ORR of 44% and the disease control rate of 89% (NCT03108495), with one patient showing a complete response [72]. While TIL therapy has shown promise as a treatment for melanoma, the presence of more than three lesions or metastasis to the liver and brain may be associated with treatment resistance [73]. Similarly, selecting the appropriate candidates may be crucial to achieve therapeutic efficacy in cervical cancer.
In recent years, therapy utilizing chimeric antigen receptor (CAR)-T cells, designed to recognize and target cancer-specific antigens, has shown success and gained approval from regulatory agencies such as the FDA for hematologic malignancies. However, the expression of cancer-specific antigens in solid tumors is limited. The first phase I/II clinical trial of mesothelin CAR-Ts targeting mesothelin-expressing tumors, including cervical and ovarian cancer (NCT01583686), was terminated because of slow accrual. The efficacy was low in this study, with only one of 15 patients showing stable disease for > 3.5 months [74]. And for solid tumors, CAR-T cell therapy carries the risk of serious on-target, off-tumor toxicity due to CAR-T cell-mediated cytotoxicity against non-malignant tissues expressing the target antigen [75].
In the first phase I/II trial of MAGE-A3 TCR-T (NCT02111850) to treat cervical cancer, a complete response was observed for > 29 months in one patient. The oncoproteins HPV-E6 and HPV-E7 are viral antigens expressed in cancers but not in healthy tissues. Therefore, they are attractive targets for genetically engineered T-cell therapy in HPV-related epithelial cancers [76]. A phase I/II trial (NCT02280811) with TCR-T targeting HPV-E6 for HPV16–positive patients, including six patients with cervical cancer, showed objective responses in two patients [77]. In another phase I trial (NCT02858310), TCR-engineered T cells targeting E7 for patients with metastatic HPV-associated epithelial cancers, including 5 patients with cervical cancer (2 of whom had been treated with ICIs), demonstrated objective clinical responses in 6 out of 12 patients [78]. These trials demonstrate an alternative treatment strategy for patients with cervical cancer, even in cases of progression after ICIs. While CAR-T cells target surface antigens, engineered TCR T cells can target intracellular antigens, but their limitation lies in HLA restrictions. Currently, HLA A*02:01 is a major target for engineered TCR T cell trials, although the distribution of HLA varies by region. The efficacy of engineered T cells for cervical cancers is currently limited and supported by clinical data, warranting further studies.
Therapeutic cancer vaccination in cervical cancer
Cancer vaccination therapy aims to stimulate the immune system by introducing tumor antigens and inducing or amplifying an antitumor immune response. The combination with ICIs with vaccination may enhance sensitivity by overcoming tumor immune resistance. Several types of tumor-specific vaccines are used. For example, peptide vaccines target specific protein fragments while DNA vaccines deliver genetic particles to produce antigens and viral vector vaccines by using modified viruses to introduce antigens. Those antigens are loaded to antigen presenting cells and stimulate T cell-based responses [79]. In the KEYNOTE-567 trial, the combination with DNA vaccination with pembrolizumab showed a better response in patients with PD-L1-positive, HPV-16, and squamous cell carcinoma than pembrolizumab alone (NCT03444376) [80]. In another trial, a HPV16 therapeutic cancer vaccine with atezolizumab showed a favorable response in PD-L1-positive patients. HPV16-circulating tumor DNA levels may predict tumor response (NCT04405349) [30]. A trial for patients with cervical cancer who relapsed after pembrolizumab is testing the efficacy of this vaccine and atezolizumab or placebo (NCT06099418). The combination of peptide vaccine, ISA101b vaccine and cemiplimab demonstrated clinical benefit especially in such patients with high PD-L1 expression [31]. Therefore, cancer vaccination therapy can be effective in appropriate patients. However, a challenge remains that the immune response does not persist and diminishes over time. These emerging therapies represent promising directions for advancing treatment options for patients with cervical cancer and warrant further exploration in clinical trials.
Conclusions
Immune-related therapies have ushered in a new era for treating cervical cancer, specifically addressing unmet clinical needs in advanced or metastatic cervical cancer. Despite notable progress, challenges persist, encompassing unresponsive tumors to immune therapies, issues related to immune therapy resistance, and the emergence of immune-related adverse events. To fully capitalize on the effectiveness of immunotherapy, extensive research efforts must be maintained from basic studies to clinical trials. This comprehensive approach will help identify suitable treatment regimens that incorporate immunotherapy for specific patient populations. Continuous research and development will play a pivotal role in refining and expanding the application of immunotherapeutic strategies, ultimately improving outcomes for individuals affected by cervical cancer.
Declarations
Conflict of interest
No author has any conflict of interest.
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