Recent updates on Sintilimab in solid tumor immunotherapy

In recent years, there have been advancements in traditional patterns of tumor therapy with the adoption of immunotherapy. Its application with or without other combined regimens has attracted attention from clinicians. Sintilimab (Tyvyt®), a highly selective fully human IgG4 monoclonal antibody, blocks the binding site of programmed cell death protein 1 (PD-1), thereby, inhibiting the interaction between PD-1 and its ligands (PD-L1/2) to restore the endogenous anti-tumor T cell responses. Sintilimab has been proven to be clinically beneficial in multiple solid tumor therapies. Combination therapy and monotherapy have shown potential and encouraging anti-tumor efficacy with controllable and acceptable toxicities. The combination therapy is more likely to be a novel and promising therapeutic option. This study provides an overview of the status of sintilimab-based clinical trials in various solid tumors.

Sintilimab (Innovent Biologics, Suzhou, China), a type of PD-1 antibodies originally co-developed by Innovent Biologics, Eli Lilly and Company, has been approved for clinical management of either relapsed or refractory classical Hodgkin's lymphoma (RR-c-HL)after more than second-line systematic chemotherapy [4]. Notably, Sintilimab was included in the 2019 edition of The Lymphoma Diagnosis and Treatment Guide of The Chinese Society of Clinical Oncology [4].

Preclinical efficacy of Sintilimab
Immune activation effects are maximized when immune checkpoint receptors are blocked and reach their saturation. This is mediated by both the concentration and the affinity of the antibody to the receptor. Despite anti-PD-1 antibodies (pembrolizumab (Keytruda, MK-3475) and nivolumab (Opdivo, MDX-1106)) exhibiting the highest affinity for human PD-1 and a lower off-rate, the PD-1 receptor occupancy of sintilimab on circulating T cells is superior, thus indicating a possibility of a continuous blockade of the PD-1-PD-L1/2 pathway [5] ( Table 1). The drug occupies the binding site for a long time even after plasma concentrations have decreased, which may lengthen its effect [5].
Previous studies established that the sustained average PD-1 receptor occupancy rates on circulating T cells in patients administered with MDX1106 (dose-independent) and sintilimab were > 70 and > 95%, respectively [6,7]. Besides, the immunogenicity of the drug affects its clinical efficacy. Protein drugs induce humoral immune responses, leading to the production of anti-drug antibodies (ADAs) and neutralizing antibodies (NAbs) upon repeated injections [8]. This phenomenon has been closely associated with the reduction in efficacy and resistance to the antibody. In humanized mouse models, sintilimab was found to exhibit better anti-tumor effects than MDX-1106 and MK-3475 [5]. These findings demonstrate the potential of sintilimab as a novel, safe, effective anti-PD-1 antibody in the cancer immunotherapy regimens.

Clinical Progress of Sintilimab in application
Lymphoma A clinical trial (NCT03114683, ORIENT-1) by Shi et al, aimed at determining the efficiency and safety of sintilimab among the Chinese population, involved intravenous administration of sintilimab (200 mg, Q3W) to RR-cHL patients. There were no fatal cases associated with the clinical trial [6]. Among patients with RR-cHL, the objective response rate (ORR) with sintilimab was 80.4%, whereas nivolumab and pembrolizumab each had 69% [5]. These outcomes positioned sintilimab as an original strategy for RR-cHL patients [6]. Regarding the results of Shi et al, Ansell SM reported identical findings.. He stated the similar durable 6-month progression-free survival rate of 77.6% for sintilimab was highlighted when compared with 77% for nivolumab and 69% for pembrolizumab [9]. Moreover, RR-cHL patients with HIV following the administration of sintilimab experienced no fatal irAEs [10].
Application of triplet therapy of sintilimab with decitabine and GDP (gemcitabine, DDP, and dexamethasone), enhanced clinical responses in a diffuse large B-cell lymphoma (DLBCL) patient with 17p deletion who was irresponsive to the 1st and the 2nd line treatments [11].

Lung Cancer Clinical trials
A trial of phase Ib in non-small lung cancer (NSCLC) was performed to evaluate the safety and efficacy of sintilimab in neoadjuvant therapy (registration number: ChiCTR-OIC-17013726). Two cycles of sintilimab (200 mg, 1st day and 22nd day) were administered to patients with resectable NSCLC at clinical-stage IA-IIIB followed by pulmonary operations after immunotherapy on the 43rd day. The patients achieved disease control rates (DCR), major pathologic response (MPR) and pathologic complete responses (pCR) of 90%, 40.5% and 16.2%, respectively. Toxicities from the administration were usually grade 1/2, indicating that patients with early-stage NSCLC could benefit from neoadjuvant immunotherapy and be well-tolerated [12]. Furthermore, it was established that a decrease in the SUV value of Positron Emission Tomography-Computed Tomography (PET-CT) may be used as a predictor for the pathological responses of NSCLC after sintilimab treatment [12].
In addition to neoadjuvant therapy, a combination of sintilimab and anlotinib (12 mg/d, 2 weeks on/1 week off) was investigated as a first-line choice for patients with NSCLC, which was a single-arm of phase I clinical trial (NCT03628521). According to the interim analysis, the ORR and disease control rate (DCR) was 77.3% and 100%, respectively. As for safety, 31.8% of 22 patients exhibited grade 3-4 treatment related adverse events (TRAE). The most frequent was hematuria. AEs were tolerable from the outcome, indicating an eminent antitumor effect due to the combination of anti-PD-1 with multi-target anti-angiogenesis drugs [13].
A randomized, double-blind, multi-center, phase III study (NCT03607539, ORIENT-11) was performed to compare sintilimab or placebo plus chemotherapy (pemetrexed and cisplatin/carboplatin) in treatmentnaïve patients with locally advanced or metastatic nonsquamous NSCLC and without sensitizing epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) genomic aberration. After a median follow-up of 8.9 months, the median progression-free survival (mPFS) of the sintilimab group against the placebo group was 8.9 and 5.0 months (p < 0.00001), respectively. The PFS rates at 6 months was 68.3% for sintlimab-combination and 42.0% for placebocombination. The PFS benefit in the sintilimabcombination group was observed in all PD-L1 subgroups. Although the median overall survival (mOS) data for the two groups were not met, it showed that the sintilimab group tended to precede the control at . With a manageable safety and tolerability profile in patients, a combination of sintilimab and chemotherapy exhibited a tremendous potential as a first-line regimen for non-squamous NSCLCs [14].
On the European Society for Medical Oncology (ESMO) congress 2020, ORIENT-12 (NCT03629925) was reported, a randomized, double-blind, phase III study to evaluate the safety and efficacy of sintilimab plus gemcitabine and platinum (GP) as a first-line option for patients with either locally advanced or metastatic squamous NSCLC. Regardless of PD-L1 expression (TPS ≥1% or < 1%), the combination was shown to benefit patients in mPFS (5.9 m vs 4.9 m, HR, 0.575; 95% CI 0.435-0.761; P = 0.00009), with an acceptable safety profile [15]. The OS data have not been reported yet.
A phase of Ib clinical trial (NCT02937116) was designed to assess the efficacy and safety of sintilimabchemotherapy as a first-line therapeutic option for both nsqNSCLC and sqNSCLC. In this study, 21 patients (pts) and 20 pts. were enrolled in nsqNSCLC group and sqNSCLC group, respectively. ORR was found to be 68.4% and 64.7%, respectively. mPFS was found to be 12.6 months and 6.5 months in the nsqNSCLC cohort and sqNSCLC cohort, respectively. Moreover, the mOS data were evaluated to be 18.9 months and 15.4 months in the nsqNSCLC group and sqNSCLC group, repectively.
It revealed that 90.5% of the participants suffered AEs in the nsqNSCLC cohort, with neutropenia being the most significant. The ratio of grade 3-4 AEs was 38.1% in the nsqNSCLC cohort, while in the sqNSCLC cohort, the AEs incidence was up to 100%, among which the most common was white blood cell (WBC) count decline. The proportion of grade 3-4 AEs was 85%. There were no fatal events associated with treatments in both two cohorts. The most frequent sintilimab-related AEs were ALT increase, most of which were grade 1-2. Comparatively, sintilimab-chemo therapy exhibited a higher incidence and severity of AEs in sqNSCLC than in nsqNSCLC.
Notably, the study revealed that PD-L1 expression, whether tumor proportion score (TPS) ≥ 1% or TPS < 1%, was not correlated with clinical response, and neither did the tumor mutation burden level (TMB). A high TCR Change (TCRC) clonality (> 1) was significantly associated with a better OS, while a low TCRC diversity (< 1) was closely related with a superior PFS [16].
Hitherto, a combination of sintilimab and chemotherapy has been used in advanced NSCLC. Unlike previous, studies that deemed PD-L1 expression to be a predictor for the evaluation of tumor efficacy postimmunotherapy [17], the predictive role of this parameter might be overturned upon sintilimab administration on patients with NSCLC. This outcome requires more large-scale clinical trials to be confirmed.

Case series
An elderly man diagnosed with stage IVb lung adenocarcinoma without the driver-gene mutation achieved a partial remission (PR) after being administered with a total of five cycles of sintilimab (Q3W, 200 mg) combined with pemetrexed plus carboplatin. The curative effect lasted for about 3 months after the discontinuation of sintilimab with chemotherapy due to cardiac and skin adverse events. However, the PFS was over 9 months [18], which coincided with the outcome of ORIENT-11 [14].
Not only the combination of sintilimab with GP but also the administration of sintilimab with nedaplatin plus paclitaxel on a stage IIIB squamous NSCL C(T3N2M0) patient showed an encouraging anti-tumor effect. After 3 cycles of treatments, the TPS of the patient dropped from 80% to 0% [19], demonstrating the potential therapeutic value of sintilimab in resectable NSCLC. In another study, a combination of sintilimab plus bevacizumab was administered on a stage IIIB lung adenocarcinoma patient with EGFR exon 19 del mutation to achieve a 6-month PFS, thus suggesting tolerance as well as safety [20].
Apart from NSCLC, sintilimab was used against small cell lung cancer (SCLC). The patient responded well because the sum of the diameter of the target lesions reduced by 12.23% following two cycles of sintilimab (3.5 mg/kg) along with docetaxel (1.5 mg/kg). However, due to paraneoplastic neurological syndromes (PNSs), sintilimab efficacies were terminated [21].

Hepatocellular carcinoma
The regimen of sintilimab (200 mg, Q3W) and IBI305 (a bevacizumab biosimilar, 15 mg/kg, Q3W) was once used to manage on a patient with HBV-associated HCC multiple pulmonary metastases, low microsatellite instability (MSI-L), high PD-L1 expression and TMB-L. In this patient, there was a complete remission (CR) after 2 cycles of administration and the level of alpha-fetoprotein (AFP) decreased from 1181.46 ng/ml to normal. The liver function of the patient remained Child-Pugh A throughout [22].
A combination of atezolizumab and bevacizumab was approved as a first-line therapeutic choice for advanced or metastatic HCC [23]. Recently, a phase II clinical trial of sintilimab (200 mg IV Q3W) combined with IBI305 (15 mg/kg IV Q3W) as a first-line treatment option for advanced HCC (NCT03794440, ORIENT-32) was performed by Fan et al. They showed that mPFS reached 8.4 months (95% CI, 5.6, not reached) but not OS. DCR was a preeminent 83.3%, while ORR was 25%, with an acceptable safety profile. Since a total of 24 patients were enrolled in the phase II clinical study, a large patient population is recommended to ascertain our findings. However, a phase III clinical trial of this study to compare the efficacy of sintilimab plus IBI305 and sorafenib is ongoing [24].

Cervical Cancer
For patients previously subjected to multiple chemotherapy sessions, recurrent or metastatic advanced cervical cancer (CC) (PD-L1 expression>1%, ECOG of 0-1), sintilimab (200 mg, intravenously, Q3W) combined with anlotinib (10 mg orally, QD, d1-14; every 21 days) was performed until disease progression, death or intolerable toxicity (ChiCTR1900023015). The study set ORR as the primary endpoint, while OS, PFS, and DCR were determined as the secondary endpoints. The maximum ORR and DCR were 54.5% and 100%, respectively. The mPFS and mOS had not been met by then, while the original regimen was deemed to be tolerable given that the most common AEs were G1/2 [29]. Due to their affordability, both sintilimab and anlotinib from China, are potential drugs for use as a combination regimen for CC.

Other types of tumors
As the second-line option after chemotherapy, CR was achieved after the application of 3 cycles of sintilimab (200 mg Q3W) on an advanced intrahepatic cholangiocarcinoma (ICC) patient with low microsatellite instability (MSI-L) and TMB. Sintilimab was discontinued due to the adrenal insufficiency attack after a total of 34 cycles of ICIs, which was relieved by hydrocortisone (20 mg/d) administration [30]. Furthermore, as a third-line strategy, a trial of sintilimab combined with tegafurgimeracil-oteracil potassium capsules was performed on an ICC case with multiple metastases. PR was achieved after 6 cycles of treatment, and the survival quality of the patient was enhanced significantly [31].
Apart from the common cancer types, sintilimab was involved in suppressing tumor progression on a KRAS positive patient with hepatoid adenocarcinoma (HAC), a sort of rare tumor secreting AFP with morphological similarities to HCC, and eventually achieved a 52-month OS [32].
Analysis of the above clinical trials ( Table 2) and specific cases showed the potential of sintilimab as an equivalent to pembrolizumab and nivolumab.

Adverse effects
Not only effectiveness but also safety is of concern when using sintilimab in solid tumors. ICIs activate the immune system in patients with cancer and promote the in vivo killing effect of T cells. Excessive activation of the immune-system leads to immune-related adverse events (irAEs) in the human body [33]. Primary causes of irAEs mechanism are the disturbance of immune balance, which might be explained by several potential hypotheses. For instances, when immune cells are overactive, cytotoxic T cells cross-react between tumor and normal cells. In addition, the increased inflammatory factors as well as the rise in the number of auto-immune antibodies, explain this phenomenon [34][35][36]. The irAEs are characterized by diarrhea, hepatitis, rash, pneumonia, thyroid dysfunction and others [33].
Anti-PD-1/PD-L1 blockades presented a high synergistic effect when incorporated with other treatments [41,42]. Previous studies revealed the anti-angiogenesis drugs potential to improve the efficacy of immunotherapy by reducing tumor hypoxia, improving perfusion, and reforming the tumor microenvironment [43,44]. For example, clinical trials on the treatment of advanced HCC using immune checkpoint inhibitors alone exhibited a poor efficacy [45,46]. However, immunotherapy combined with anti-angiogenesis therapy presented a synergistic effect on the mechanism of action [23,46], which was proved by a trial of IMbrave 150 in unresectable HCC patients [23]. Strategies that combine other types of immunomodulators, chemotherapy, and molecular targeted treatments either in vivo or in vitro are ongoing [5].
Over the past few decades, clinical trials of new drugs in China were lagging behind other regions and their approval in the Chinese market were delayed for years. With the advance of the National Medicine Products Administration (NMPA) reform, more international pharmaceutical companies will perform clinical trials in China after realizing the globalization of drug development [47]. Interestingly, sintilimab can potentially benefit patients from underdeveloped areas or developing countries with promising anti-tumor effects as well as its affordability.
Several sintilimab-based clinical trials on malignancies are ongoing in multi-center in China, among the key trials are elaborated in (www.clinicaltrials.gov/)( Table 3):

Conclusions
This article summarizes the progress of sintilimab in the field of cancer treatments, generalizing the efficacy and safety of sintilimab alone or combined regimens in multiple solid tumors. With the promising potential and application prospect of sintilimab, a vast number of multicenter, large-scale prospective clinical trials are going ahead in China to further determine its safety and effectiveness for cancer therapy. Hitherto, sintilimab has only been approved for use in RR-cHL, and it could be expected to be approved for more cancer types and admitted to realize its globalization.