Envafolimab – first PD-1/PD-L1 antibody to be administered by subcutaneous injection for microsatellite instability-high or deficient mismatch repair advanced solid tumors

ABSTRACT

Introduction

Programmed death-1/programmed death-ligand 1 (PD-1/PD-L1) inhibitors mobilize and activate the anti-tumor activity of the immune system by blocking the inhibitory effects of the PD-1/PD-L1 signaling pathway in T cells. Several anti-PD-1 or -PD-L1 monoclonal antibodies have been approved for the treatment of advanced solid tumors. However, most of immune checkpoint inhibitors (ICIs) are administered via intravenous infusion, which is inconvenient and leads to unsatisfactory patient compliance in the treatment process. Therefore, subcutaneous envafolimab is a potential treatment modality for advanced solid tumors.

Area covered

A phase I clinical trial showed that the safety and pharmacokinetic profiles of envafolimab were similar to those of other traditional antibodies. Additionally, clinical findings from a phase II trial revealed that envafolimab monotherapy exhibited satisfactory clinical therapeutic effects and no significant adverse events in patients with microsatellite instability-high/deficient mismatch Repair (MSI-H/dMMR) solid tumors who failed at least one line of prior systemic therapy.

Expert opinion

Subcutaneous envafolimab may serve as a more convenient and acceptable treatment modality than those approved PD-1/PD-L1 inhibitors for patients with an advanced solid tumor, which may revolutionize the modes of immunotherapy in the future.

KEYWORDS:

• Advanced solid tumors
• envafolimab
• subcutaneous injection
• anti-PD-L1
• microsatellite instability-high/deficient mismatch repair

1. Introduction

Immune checkpoints, represented by programmed death-1/programmed death-ligand 1 (PD-1/PD-L1) expression, are important pathways for the immune system to maintain self-tolerance and prevent autoimmunity. Additionally, the PD-1/PD-L1 pathway prevents excessive immune activation, while cancer cells escape immune detection by up-regulating PD-L1 expression. In brief, tumors have developed immunosuppressive mechanisms to dampen the innate and effector arms of the immune system, thus compromising most of the proposed immunotherapeutic strategies.

PD-1/PD-L1 inhibitors mobilize the anti-tumor activity of the immune system by blocking the inhibitory effects of the PD-1/PD-L1 signaling pathway in T cells [1]. Currently, several anti-PD-1 and -PD-L1 monoclonal antibodies (mAbs) have been approved for the treatment of various advanced solid tumors, further improving patient survival. However, most of immune checkpoint inhibitors (ICIs) are administered via intravenous infusion, leading to inconvenience and unsatisfactory compliance in patients. As the first subcutaneous PD-L1 inhibitor, envafolimab showed more satisfactory efficacy and safety profiles than other approved PD-1/PD-L1 inhibitors Box 1) [2]. Lastly, ICIs administered via subcutaneous injection may improve the treatment modes for patients with tumors, particularly for those who are in a stable condition and require long-term immunotherapy.

Overall objective response rate (ORR) in patients with tumors receiving PD-1/PD-L1 inhibitor monotherapy is limited. Therefore, it is important to detect biomarkers related to the prediction of efficacy and screen potential therapeutic benefit populations before PD-1/PD-L1 inhibitor therapy. Biomarkers that can predict the clinical benefit in patients with cancers include PD-L1, microsatellite instability-high/deficient mismatch repair (MSI-H/dMMR), and tumor mutational burden (TMB) [3–5], of which MSI-H is a highly studied marker. The proportion of patients with MSI-H differs greatly among different advanced solid tumors. Statistical research reveal that MSI-H is more frequently observed in endometrial carcinoma, colorectal cancer, and gastric cancer [6,7]. Currently, PD-1/PD-L1 inhibitor therapy is widely accepted to be efficacious in patients with gastric or colorectal cancer, combined with MSI-H/dMMR in their tumor tissues.

2. Overview of envafolimab

2.1. Introduction of drug structure and chemistry

Traditional antibodies are difficult to produce, available only in limited quantities, and ineffective as enzymatic labels. Nanobodies with single-domain antibodies (sdAbs) offer an alternative, more promising tool to circumvent these limitations [8]. Furthermore, camelids produce functional antibodies composed of heavy chains that bind to their antigens via a single domain variable fragment known as a nanobody [9]. Envafolimab is a novel homodimer fusion of a humanized single-domain PD-L1 antibody and human immunoglobulin G1 (IgG1) Fc fragment covalently linked by interchain disulfide bonds. However, the structure of envafolimab differs from that of traditional antibodies, such as Pembrolizumab and Nivolumab, in which the antibody-binding region contains both heavy and light chains [10]. As a heavy chain-only antibody from camels, envafolimab is a sdAb with a molecular weight half that of conventional antibodies. Moreover, the antigen-binding region of envafolimab is the main biologically active region for its targeted binding and blocking functions, which compete with PD-1 for the same flat surface on PD-L1, primarily via a single surface loop composed of 21 amino acids. In brief, the unique structure of envafolimab provides a more flexible mechanism for binding antigens and stronger binding ability to PD-L1 than PD-1 (approximately 1000 times), resulting in higher binding affinity and specificity. Lastly, the excellent structure stability, low molecular weight, and strong tissue penetration of envafolimab permit for subcutaneous injection [11].

2.2. Mechanisms of drug action

Envafolimab blocks inhibitory signal transmission to T cells and promotes T cell activation by blocking both PD-1/PD-L1 and PD-L1/cluster of differentiation 80 (CD80) signaling pathways. Pre-clinical findings revealed a significant tumor-inhibitory effect of envafolimab at low doses. Furthermore, envafolimab exhibited a significantly better anti-tumor effect than that of Durvalumab at the same dose. Moreover, a functional test performed in a mixed lymphocyte reaction (MLR) demonstrated that envafolimab activates cluster of differentiation 4 (CD4)-positive T cells to release interferon-gamma (IFN-γ), and the activation of envafolimab is more effective than that of Durvalumab at the same molar amount [11]. In addition to multiple tumor cells, PD-L1 is also expressed in non-hematopoietic cells including corneal epithelial cells, vascular epithelial cells, and activated T, B, dendritic, and other immune cells [12,13]. Therefore, the Fc segment of envafolimab was modified to prevent antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) activities resulting in reduced adverse events.

2.3. Clinical efficacy

2.3.1. Phase I clinical trial

A phase I clinical trial of envafolimab (ClinicalTrials.gov, NCT02827968) investigated the safety and pharmacokinetics of envafolimab in 28 patients with previously treated advanced solid tumors in the United States, including 6 patients with prostate cancer, 5 patients with colorectal cancer, 3 patients with intrahepatic biliary tract cancer, 2 patients with non-small cell lung cancer (NSCLC), 2 patients with breast cancer (BC), 2 patients with cervical cancer, 1 patient with bladder cancer, 1 patient with esophageal cancer, 1 patient with head and neck cancer, 1 patient with liver cancer, 1 patient with melanoma, 1 patient with neuroendocrine tumor, 1 patient with gastrointestinal stromal tumor, 1 patient with pancreatic cancer. All patients received envafolimab (0.01 ~ 10 mg/kg) weekly during the dose-escalation period (n = 18). No dose-limiting toxicity was observed, and the median time to maximum blood concentration was 4–7 days. During the dose-exploration period (n = 10), patients received 300 mg of envafolimab once every four weeks via subcutaneous injection. The half-life after the first dose was approximately 14 days, which was extended to 23 days at the steady state. Additionally, envafolimab showed a similar pharmacokinetic profile with other traditional antibodies, indicating that an extended dosing interval was feasible. Of 28 patients, none achieved complete remission (CR), and 3 patients achieved partial remission (PR) (10.7%), including two patients who achieved continuous response (24.9–74.1 weeks). The most common treatment-emergent adverse events (TEAEs) included fatigue (29%), nausea (18%), diarrhea (14%), and hypothyroidism (14%). Grade 3 drug-related TEAEs occurred in three patients, and no grade ≥ 4 drug-related TEAEs or injection site reactions were observed [14].

2.3.2. Phase II clinical trial

A phase II clinical trial of envafolimab (ClinicalTrials.gov, NCT03667170) was performed at 25 clinical sites across China and enrolled 103 patients with microsatellite instability high/defective mismatch repair (MSI-H/dMMR) tumor, including 65 patients with colorectal cancer, 18 patients with gastric cancer, and 20 patients with other solid tumors. The most frequent cancer types in 20 patients with other solid tumors were endometrial cancer (n = 6), hepatocellular cancer (n = 2), and hepatocholangiocarcinoma (n = 2). All patients enrolled in this phase II trial who failed at least one line of prior systemic therapy received 150 mg of envafolimab by subcutaneous injection once a week after enrollment until disease progression (PD) or intolerable toxicity. For all populations, the median follow-up duration was 11.5 months, ORR was 42.7%, the disease control rate (DCR) was 66.0%, the median progression-free survival (PFS) was 11.1 months, the median duration of response (DoR) and median overall survival (OS) were not reached, and the 12-month OS rate was 74.6%. Moreover, the ORRs of colorectal cancer, gastric cancer, and other solid tumors were 43.1%, 44.4%, and 40.0%, respectively, and those of patients with colorectal cancer who failed doublet and triplet therapy were 62.5% and 31.7%, respectively. In conclusion, these results suggested that envafolimab monotherapy exhibited satisfactory therapeutic effects on patients with MSI-H/dMMR advanced solid tumors who failed at least one line of prior systemic therapy. In terms of adverse events, 37% of the patients had at least one grade 3–4 TEAE, 8% of patients had grade 3–4 immune-related adverse events (irAEs), and no immune-related pneumonitis or colitis was reported. Grade 3–4 drug-related TEAEs, primarily leukopenia (17%), asthenia (17%), rash (16%), hypothyroidism (16%), hyperthyroidism (12%), decreased neutrophil count (12%), and anemia (12%) were observed in 16% of patients. Three grade 5 TEAEs were recorded and considered not drug-related. No infusion-related reactions wasobserved in any of the patients, except for minor injection site reactions (grades 1–2) observed in some patients (9%). In general, envafolimab exhibited favorable tolerability and safety in the treatment for advanced solid tumors [2].

2.3.3. Comparison between envafolimab and other PD-1/PD-L1 inhibitors

In the completed and ongoing clinical trials of MSI/dMMR tumors, one study investigated Pembrolizumab as a first-line treatment in colorectal cancer (KEYNOTE177) [15]. Other trials are intended to evaluate the efficacy of PD-1/PD-L1 mAb in previously treated cancer types, including colorectal cancer, endometrial cancer, and gastric cancer with a high proportion of MSI. The data from different studies are generally comparable, and the differences may be partly associated with the different types of cancers and small size (Table 1). A phase II clinical trial of envafolimab included patients with previously treated MSI/dMMR tumors, mainly colorectal cancer (65/103 patients). Envafolimab was comparable to Pembrolizumab, Nivolumab, and Durvalumab in terms of efficacy and compliance (Table 1), regardless of cancer types. In terms of adverse events, the incidences of grade ≥3 TEAEs and irAEs related to envafolimab were at around 20% and 10%, respectively, which were generally comparable to those for other PD-1/PD-L1 mAbs (Table 2). However, among patients treated with Pembrolizumab, approximately 2–7% developed immune enteritis, and 1–5% developed immune pneumonitis, while no immune pneumonitis or enteritis was observed among patients treated with envafolimab, possibly related to the functional reserve between PD-1 and programmed death-ligand 2 (PD-L2) [16,17]. In addition, due to the subcutaneous injection, envafolimab would not cause infusion reactions compared with that in other ICI treatments (0% vs. 1–4%).

Table 1. Efficacy comparison of different immune checkpoint inhibitors (ICIs) for MSI-H/dMMR Tumors.

							DoR		PFS		OS
Reference	Trial/NCT number	Agent	Tumor types	ORR (%)	DCR (%)(SD)	Median time to response	% at 12 m	median	% at 12 m	median	% at 12 m	median
[2]	NCT03667170	Envafolimab	≥2nd cancers, MSI, n = 103	42.7	66.0(23.3)	NA	92.2	NR	48.5	11.1 m	74.6	NR
[15]	KEYNOTE177(NCT02563002)	Pembrolizumab	1st CRC, MSI, n = 153	43.8	64.7(20.9)	2.2 m	N/A	NR	55.3	16.5 m	78.0	NR
[18]	KEYNOTE164(NCT02460198)	Pembrolizumab	≥2nd CRC, MSI, n = 63	34.9	55.6(20.7)	3.9 m	NA	NR	41.0	4.1 m	76.0	47.0 m
			≥3rd CRC, MSI, n = 61	32.8	50.8(18)	4.3 m	NA	NR	34.0	2.3 m	72.0	31.4 m
[19]	KEYNOTE059 (NCT02335411)	Pembrolizumab	≥3rd GC, MSI, n = 7	57.1	71.4(14.3)	NA	NA	NR	NA	NR	71.0	NR
[19]	KEYNOTE061(NCT02494583)	Pembrolizumab	2nd GC, MSI, n = 15	46.7	86.7(40)	NA	NA	NR	NA	17.8 m	73.0	NR
[19]	KEYNOTE062(NCT02494583)	Pembrolizumab	1st GC, MSI, n = 14	57.1	78.6(21.5)	NA	NA	21.2 m	NA	11.2 m	79.0	NR
[20,21]	KEYNOTE158(NCT02628067)	Pembrolizumab	≥2nd non-CRC, MSI-H/dMMR, n = 233	34.3	52.4(18.1)	2.1 m	86.9	NR	33.9	4.1 m	60.7	23.5 m
[22]	NCT02899793	Pembrolizumab	≥2nd EC, MSI, n = 24	58.3	83.3(25)	NA	NA	NA	66.0	23.5 m	91.0	40.0 m
[23]	NCT02673333	Pembrolizumab	ACC, MSI, n = 6	33.3	66.7(33.4)	NA	NA	NA	NA	NA	NA	NA
[24]	CHECKMATE142(NCT02060188)	Nivolumab	≥2nd CRC, MSI, n = 74	31.1	68.9(37.8)	2.8 m	NA	NR	50.4	NA	73.4	NR
[25]	CHECKMATE032(NCT01928394)	Nivolumab	≥2nd EG, MSI, n = 7	28.6	71.4(42.8)	NA	NA	NA	NA	NA	NA	14.8 m
[26]	EAY131-Z1D (NCT02465060)	Nivolumab	≥2nd non-CRC, MSI, n = 42	36	57(21)	NA	NA	NA	46.2	6.3 m	NA	17.3 m
[27]	NCT01693562	Durvalumab	≥2nd cancers, MSI, n = 62	22.6	48.4(25.8)	NA	NA	NA	35.0	5.0 m	N/A	24.0 m
			≥2^nd CRC, MSI, n = 36	22.2	47.2(25)	NA	NA	NA	38.0	6.0 m	N/A	NR
[27]	NCT02227667	Durvalumab	≥2nd CRC, MSI, n = 11	27.3	NA	NA	NA	NA	36.0	6.0 m	NA	NR
[28]	PHAEDRA(NCT03015129)	Durvalumab	AEC, MSI, n = 35	47.2	63.9(16.7)	NA	NA	NA	NA	8.3 m	71.0	NA
[29,30]	GARNET(NCT02715284)	Dostarlimab	≥2nd EC, MSI, n = 108	43.5	55.6(12.1)	NA	90.9	NR	NA	NR	NA	NR
			≥2nd non-EC, MSI, n = 106	38.7	NA	NA	91.0	NR	NA	NR	NA	NR
[31]	NCT03150706	Avelumab	≥2nd CRC, MSI, n = 21	28.6	90.5(61.9)	NA	NA	NA	36.4	8.1 m	66.7	NR
[32]	NCT02912572	Avelumab	≥2ndEC, MSI, n = 15	26.7	53.3(26.6)	NA	NA	NA	NA	4.4 m	NA	NR
[33]	NCT02908906	Cetrelimab	≥2nd CRC, MSI, n = 21	23.8	61.9(38.1)	NA	NA	NA	NA	NA	NA	NR
[34]	ChiCTR-OIC-17013249	Camrelizumab	≥2ndcancers, MSI, n = 12	66.7	100.0 (33.3)	2.0 m	NA	NR	83.3	NR	90.0	NR
[35]	NCT03704246	HX008	≥2nd cancers, MSI, n = 100	47.7	75.6 (27.9)	NA	NA	NA	52.7	NR	NA	NR
[36]	NCT03941574	HLX10	≥2nd cancers, MSI, n = 68	38.2	67.6 (29.4)	NA	NA	NR	NA	NR	NA	NR
[37]	NCT03736889	Tislelizumab	≥2nd cancers, MSI, n = 74	45.9	71.6(25.7)	NA	NA	NR	NA	NR	NA	NR

Objective response rate (ORR); Disease control rate (DCR); Duration of response (DoR); Overall survival (OS); Immune-related adverse events (IrAEs); Dendritic cells (DC); Colorectal cancer (CRC); Gastric cancer (GC); Endometrial cancer (EC); Adrenocortical carcinomas (ACC); Advanced endometrial cancers (AEC); Adenocarcinoma of the esophagogastric junction (AEG). Not available (NA); Not reached (NR); Progression-free survival (PFS); Microsatellite instability (MSI); Standard deviation (SD).

Table 2. Comparison of adverse events of different immune checkpoint inhibitors for MSI-H/dMMR tumors.

				TEAEs		Drug-related TEAEs		IrAEs				Infusion-related reactions
Reference	Trial/NCT number	Agent	Tumor types	All grades	Grade ≥3	All grades	Grade ≥3	All grades	Grade ≥3	Pneumonitis	colitis
[2]	NCT03667170	Envafolimab	≥2nd cancers	96.1%	39.8%	84.5%	15.5%	42.7%	7.8%	0.0%	0.0%	0.0%
[15]	KEYNOTE177	Pembrolizumab	1st CRC	97.4%	56.2%	79.7%	21.6%	30.7%	9.2%	3.9%	6.5%	2.0%
[11]	KEYNOTE164	Pembrolizumab	≥2nd CRC	-	-	69.8%	12.7%	36.5%	3.2%	4.8%	1.6%	1.6%
			≥3rd CRC	-	-	62.3%	16.4%	21.3%	6.6%	4.9%	1.6%	1.6%
[20,21]	KEYNOTE158	Pembrolizumab	≥2nd non-CRC	-	-	64.8%	14.6%	23.2%	6.0%	3.9%	3.9%	0.9%
			≥2nd EC	-	-	75.6%	12.2%	27.8%	6.7%	1.1%	3.3%	4.4%
[22]	NCT02899793	Pembrolizumab	≥2nd EC	-	-	83.3%	23.3%	-	-	-	-	-
[24]	CHECKMATE142	Nivolumab	≥2nd CRC	98.6%	59.5%	70.3%	21.6%	-	-	-	-	-
[27]	NCT01693562	Durvalumab	≥2nd cancers	-	-	59.7%	3.2%	-	-	-	-	-
[29]	GARNET	Dostarlimab	≥2nd EC	95.3%	48.1%	63.6%	13.2%	-	-	-	-	-
			≥2nd non-EC	-	-	68.8%	8.3%	-	-	-	-	-
[31]	NCT03150706	Avelumab	≥2nd CRC	-	-	72.7%	18.2%	-	-	-	-	-
[31]	NCT02912572	Avelumab	≥2nd EC	-	-	71.0%	19.4%	-	-	-	-	-
[34]	ChiCTR-OIC-17013249	Camrelizumab	≥2nd cancers	100.0%	58.3%	100.0%	41.7%	-	-	-	-	-
[35]	NCT03704246	HX008	≥2nd cancers	-	-	77.0%	12.0%	15.0%	-	-	-	-
[36]	NCT03941574	HLX10	≥2nd cancers	97.2%	49.15	-	-	48.1%	9.3%	-	-	-
[4]	NCT03736889	Tislelizumab	≥2nd cancers	-	47.5%	-	-	-	5.0%	-	-	-

TEAEs, treatment-emergent adverse events; IrAEs, immune-related adverse events; CRC, colorectal cancer; EC, endometrial cancer.

3. Conclusion

As the first-approved subcutaneous ICI, envafolimab can improve the convenience of immunotherapy and compliance with tolerable safety for patients with advanced solid tumors, which may bring about new changes and provide new insights into the modes of immunotherapy in the future.

4. Expert opinion

4.1. Changes in treatment modes for patients with advanced solid tumors

Previous studies demonstrated that the efficacy, safety, and treatment convenience of envafolimab is comparable with other ICIs. Since immunotherapy may control the disease for a relatively long period, specially for immunotherapy-sensitive subtypes, such as MSI-H tumors. Furthermore, subcutaneous injection may prevent the need to go to the hospital ward or outpatient clinic for infusion therapy in patients who only require ICI monotherapy, which is more convenient and time-saving. As there are no special requirements for the subcutaneous injection of envafolimab, the injection can be completed in only 30s. Moreover, envafolimab has many advantages, including high stability, easy of store and transport (no requirement of cold chain transportation). Therefore, subcutaneous injection of envafolimab may be completely administered by community doctors or as domiciliary treatments, which greatly reduces the frequency of hospital visits and transforms the treatment modes for patients with cancer. Subcutaneous envafolimab not only effectively reduces the burden of medical resources but also provides patients with more convenient and flexible treatment mode options, as well as reduces the risk of a novel coronavirus in the face of the COVID-19 pandemic and other public health events. Unfortunately, previous protocols of envafolimab did not consider the convenience of drug administration by subcutaneous injection, and thus quality of life or economic evaluations were not designed. Therefore, direct clinical data on envafolimab remain rare from the perspective of social economic perspective.

4.2. Combination of envafolimab with other intravenous PD-1/PD-L1 inhibitors

Although subcutaneous envafolimab monotherapy has been approved for the treatment of patients with metastatic MSI-H/dMMR advanced solid tumor, combination therapy with other intravenous ICIs may gradually show great advantages in terms of efficacy and safety for the treatment of various advanced solid tumors. As a PD-L1 mAb administered by subcutaneous injection, the use of envafolimab in combination with other intravenous ICIs remains to be further explored. An in vitro study demonstrated that the envafolimab enters the tumor quickly via subcutaneous injection, and clinical trials revealed that the onset time of envafolimab was similar to that of other immune drugs. Moreover, the synergistic effects between two drugs administered via different routes may differ from those of two drugs both administered via intravenous infusion. Therefore, clinical evaluation of combination therapies is warranted. Related problems may be avoided if subcutaneous forms are developed for other immune drugs.

4.3. Application of immunotherapy in patients with high risk of adverse events

Serious irAEs are important factors that limit immunotherapy. Although adverse events, including immune pneumonitis, immune enteritis, or severe toxicity, are relatively infrequent in other treatment modes, weekly subcutaneous injection improves tolerability. Therefore, envafolimab may be suitable for individuals at high risks of irAEs, such as elderly patients with interstitial lung disease, and those who discontinued treatment due to AEs despite previous use of other ICIs. Careful evaluation is required before envafolimab treatment. If ethically permitted, further clinical trials on envafolimab in individuals who require immunotherapy and are at high risks of AEs should be further conducted. Such clinical trials are at high risks, which require careful evaluation, strict protocol design, and adequate subject protection measures.

Table

Drug summary box
Drug name	Envafolimab
Phase	Phase II
Indication	Microsatellite instability-high/deficient mismatch Repair (MSI-H/dMMR) advanced solid tumors
Pharmacology description/ mechanisms of action	Monoclonal antibody/PD-L1 inhibitor
Chemical Structure	Not available
Pivotal trials	NCT02827968 [14], NCT03667170[2]

Article highlights

• Immune checkpoint inhibitors further improve the survival benefits of patients with cancer, particularly in those with microsatellite instability-high (MSI-H) advanced solid tumors.

• Envafolimab has a unique single-domain antibody structure and is the first subcutaneously injected PD-L1 antibody worldwide.

• In phase I and II clinical trials, envafolimab exhibits favorable safety and efficacy in the treatment of MSI-H advanced solid tumors.

• Envafolimab displays comparable efficacy and safety to other Immune checkpoint inhibitors in the treatment of advanced MSI-H solid tumors.

• Envafolimab may improve accessibility to immunotherapy, thus altering future treatment patterns in patients with cancer.

Declaration of interest

M Jiang and X Wang are employees of Jiangsu Simcere Pharmaceutical Co., Ltd., Nanjing, China. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Abbreviations

Programmed death-1/programmed death-ligand 1 (PD-1/PD-L1); Programmed death-ligand 2 (PD-L2); Cluster of Differentiation 80 (CD80); Cluster of Differentiation 4 (CD4); Microsatellite instability-high/deficient mismatch Repair (MSI-H/dMMR); Microsatellite instability (MSI); Adverse events (AEs); Monoclonal antibodies (mAbs); Immune checkpoint inhibitors (ICIs); Human immunoglobulin G1 (IgG1); Mixed lymphocyte reaction (MLR); Interferon-gamma (IFN-γ); Antibody-dependent cell-mediated cytotoxicity (ADCC); Tumor mutational burden (TMB); Complement-dependent cytotoxicity (CDC); Treatment-emergent adverse events (TEAEs); Objective response rate (ORR); Disease control rate (DCR); Duration of response (DoR); Overall survival (OS); Progression-free survival (PFS); Immune-related adverse events (IrAEs); Disease progression (PD); Complete remission (CR); Partial remission (PR); Dendritic cells (DC); Colorectal cancer (CRC); Gastric cancer (GC); Non-small cell lung cancer (NSCLC), Breast cancer (BC); Endometrial cancer (EC); Adrenocortical carcinomas (ACC); Advanced endometrial cancers (AEC); Adenocarcinoma of the esophagogastric junction (AEG); Single-domain antibodies (sdAbs).

Correction Statement

This article has been republished with minor changes. These changes do not impact the academic content of the article.

Additional information

Funding

This paper was funded by Jiangsu Simcere Pharmaceutical Co., Ltd. Nanjing, China.