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Oncolytic and local immunotherapy
Original research
Preliminary efficacy and safety of YSCH-01 in patients with advanced solid tumors: an investigator-initiated trial
  1. Yandong He1,
  2. Xuhong Huang2,
  3. Xiaoxia Li3,
  4. Hongwei Liu4,
  5. Min Liu5,
  6. Junjia Tao5,
  7. Yuanzhou Shan6,
  8. Hafiz Khuram Raza7,
  9. Yanqiu Liu7,
  10. Wenting Zhong7,
  11. Xue-ping Cao7,
  12. Yuan-yuan Yang7,
  13. Ruimei Li7,
  14. Xian-long Fang7,
  15. Kang-jian Zhang7,
  16. Rong Zhang8 and
  17. Feng Liu1
  1. 1Department of Urology, Affiliated Sixth People’s Hospital South Campus, Shanghai Jiao Tong University, Shanghai, China
  2. 2Department of Gynecology and Obstetrics, Affiliated Sixth People’s Hospital South Campus, Shanghai Jiao Tong University, Shanghai, China
  3. 3Department of Nursing, Affiliated Sixth People’s Hospital South Campus, Shanghai Jiao Tong University, Shanghai, China
  4. 4Department of Pneumology, Affiliated Sixth People’s Hospital South Campus, Shanghai Jiao Tong University, Shanghai, China
  5. 5Department of Ultrasound Medicine, Affiliated Sixth People’s Hospital South Campus, Shanghai Jiao Tong University, Shanghai, China
  6. 6Department of General Surgery, Affiliated Sixth People’s Hospital South Campus, Shanghai Jiao Tong University, Shanghai, China
  7. 7Department of Clinical Transformation, Shanghai Yuansong Biotechnology Company Limited, Shanghai, China
  8. 8Department of Gynecologic Oncology, Shanghai Geriatric Medical Center, Shanghai, China
  1. Correspondence to Dr Feng Liu; peakliu{at}alumni.sjtu.edu.cn; Dr Rong Zhang; rongzhang{at}163.com

Abstract

Objective To evaluate the safety and preliminary efficacy of YSCH-01 (Recombinant L-IFN adenovirus) in subjects with advanced solid tumors.

Methods In this single-center, open-label, investigator-initiated trial of YSCH-01, 14 patients with advanced solid tumors were enrolled. The study consisted of two distinct phases: (1) the dose escalation phase and (2) the dose expansion phase; with three dose groups in the dose escalation phase based on dose levels (5.0×109 viral particles (VP)/subject, 5.0×1010 VP/subject, and 5.0×1011 VP/subject). Subjects were administered YSCH-01 injection via intratumoral injections. The safety was assessed using National Cancer Institute Common Terminology Criteria for Adverse Events V.5.0, and the efficacy evaluation was performed using Response Evaluation Criteria in Solid Tumor V.1.1.

Results 14 subjects were enrolled in the study, including 9 subjects in the dose escalation phase and 5 subjects in the dose expansion phase. Of the 13 subjects included in the full analysis set, 4 (30.8%) were men and 9 (69.2%) were women. The most common tumor type was lung cancer (38.5%, 5 subjects), followed by breast cancer (23.1%, 3 subjects) and melanoma (23.1%, 3 subjects). During the dose escalation phase, no subject experienced dose-limiting toxicities. The content of recombinant L-IFN adenovirus genome and recombinant L-IFN protein in blood showed no trend of significant intergroup changes. No significant change was observed in interleukin-6 and interferon-gamma. For 11 subjects evaluated for efficacy, the overall response rate with its 95% CI was 27.3% (6.02% to 60.97%) and the disease control rate with its 95% CI was 81.8% (48.22% to 97.72%). The median progression-free survival was 4.97 months, and the median overall survival was 8.62 months. In addition, a tendency of decrease in the sum of the diameters of target lesions was observed. For 13 subjects evaluated for safety, the overall incidence of adverse events (AEs) was 92.3%, the overall incidence of adverse drug reactions (ADRs) was 84.6%, and the overall incidence of >Grade 3 AEs was 7.7%, while no AEs/ADRs leading to death occurred. The most common AEs were fever (69.2%), nausea (30.8%), vomiting (30.8%), and hypophagia (23.1%).

Conclusions The study shows that YSCH-01 injections were safe and well tolerated and exhibited preliminary efficacy in patients with advanced solid tumors, supporting further investigation to evaluate its efficacy and safety.

Trial registration number NCT05180851.

  • Solid tumor
  • Response Evaluation Criteria in Solid Tumors - RECIST
  • Oncolytic virus

Data availability statement

Data are available upon reasonable request. The data and materials that supported the findings in this research are available upon reasonable request to the corresponding author.

http://creativecommons.org/licenses/by-nc/4.0/

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See http://creativecommons.org/licenses/by-nc/4.0/.

https://doi.org/10.1136/jitc-2024-008999

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    WHAT IS ALREADY KNOWN ON THIS TOPIC

    • Oncolytic virus therapy can specifically and effectively target and destroy cancer cells, offering advantages such as high tumor-targeting efficiency, low side effects, broad indications, and cost-effectiveness. However, the clinical data on their efficacy is limited.

    WHAT THIS STUDY ADDS

    • This is the first human study of oncolytic adenovirus, YSCH-01, which was administered to subjects with advanced solid tumors via intratumoral injection.

    • This study showed that YSCH-01 intratumoral injections were effective against advanced solid tumors, with an overall response rate of 27.35% and a disease control rate of 81.8%, while its safety was comparable to other similar drugs.

    HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY

    • This study shows the safety and preliminary efficacy of YSCH-01 in subjects with advanced solid tumors and will pave the way for future phase I and II studies.

    Introduction

    Cancer is a leading global cause of mortality, accounting for nearly 10.0 million deaths, or approximately one-sixth of worldwide deaths in 2020.1 Among the most frequently diagnosed cancers are breast, lung, colon, rectal, and prostate cancers. Advanced solid tumors, marked by aggressive and invasive growth, present a significant global health challenge due to their high incidence and substantial impact on morbidity and mortality. While surgery remains the primary option for early-stage tumors, it often falls short of complete eradication. Radiotherapy and chemotherapy can induce tumor cell tolerance, leading to relapse and poor prognosis. Molecular targeted therapies have limitations, with some tumors remaining unresponsive and adverse reactions occurring. Additionally, gene mutations and tumor heterogeneity contribute to resistance responses, diminishing long-term treatment efficacy. Notably, patients undergoing targeted therapies often develop drug resistance, curtailing therapeutic effectiveness.2

    Oncolytic viruses (OVs), either naturally occurring or genetically modified, selectively replicate within tumor cells, inducing cell lysis while maintaining safety in normal cells. These viruses exert antitumor effects through various mechanisms, offering advantages such as high tumor-targeting efficiency, low side effects, broad indications, and cost-effectiveness. However, clinical data have revealed limitations in the antitumor effects of oncolytic adenoviruses relying solely on the viral vector.3 Professor Liu Xinyuan introduced the “Cancer Targeting Gene-Viro-Therapy (CTGVT)” strategy, involving the insertion of synergistic therapeutic genes into the OV vector. This strategy allows therapeutic genes to replicate and express specifically within the tumor, enhancing the oncolytic adenovirus’ antitumor effects.4 In this study, we aimed to evaluate the safety and preliminary efficacy of YSCH-01 (Recombinant L-IFN adenovirus) in subjects with advanced solid tumors. YSCH-01 is a genetically modified oncolytic adenovirus developed by Shanghai Yuansong Biotechnology, based on the aforementioned CTGVT strategy. This was a single-center investigator-initiated clinical trial and the first human study of YSCH-01.

    Methods

    Study objectives

    Primary objectives

    1. To evaluate the safety/tolerability of YSCH-01 injections for the treatment of patients with recurrent/refractory advanced solid tumors.

    2. To preliminarily determine the recommended clinical dose of YSCH-01 injection.

    Secondary objectives

    1. To observe the pharmacokinetics (PKs)/pharmacodynamics (PDs) in patients who received YSCH-01 injection.

    2. To preliminarily evaluate the efficacy of YSCH-01 injection in the treatment of recurrent/refractory advanced solid tumors.

    3. To evaluate immunogenicity in patients who received YSCH-01 injection.

    Study design and participants

    This was a single-center, open-label, investigator-initiated trial of YSCH-01 conducted in patients with advanced solid tumors. Detailed inclusion and exclusion criteria can be found in online supplemental file 1. The study consisted of two distinct phases: (1) the dose escalation phase and (2) the dose expansion phase. In the dose escalation phase, three dose groups were established, comprizing 5.0×109 viral particles (VP)/subject, 5.0×1010 VP/subject, and 5.0×1011 VP/subject. The typical 3+3 dose escalation design was employed to determine the maximal tolerable dose (MTD), which, in turn, guided the establishment of the recommended expansion dose (RED). The primary focus of the dose expansion phase was to further evaluate the safety, PKs, preliminary efficacy, and immunogenicity of YSCH-01 in patients presenting with diverse types of tumors.

    Supplemental material

    Study duration

    This study consisted of a screening period, a treatment period, and a follow-up period. The screening period started from the day the subject signed the informed consent form (Day −21) to Day −1 before the first dose. Eligible subjects received YSCH-01 injection until any of the following occurred: lack of benefits in the opinion of the investigator, intolerable toxicity, subject withdrawal of consent, progressive disease, subject death, loss to follow-up, discontinuation for the best interest of the patient in the opinion of the investigator, or completion of the 22-week (dose escalation phase)/20-week (dose expansion phase) treatment period, whichever occurred first. The follow-up period consisted of safety follow-up and survival follow-up. Subjects who withdrew from the study/discontinued the treatment for any reason were required to return to the study site for safety follow-up 28 days (±7 days) after the last dose. Thereafter, patients entered the survival follow-up period, during which they underwent survival follow-up every 12 weeks until the subject withdrew consent, death, loss to follow-up, initiation of an antitumor therapy other than that specified in the protocol, or the end of the study, whichever occurred first.

    Dose and administration

    The study treatment for each dose group in the dose escalation phase was divided into a single-dose phase and a multiple-dose phase. Subjects received one single dose of YSCH-01 and followed a dose limiting toxicity (DLT) observation period of 4 weeks. In case no DLTs occurred, subjects would enter multidose, where they received medications once a week. Subjects received the corresponding dose (5.0×109–5.0 × 1011 VP/subject) according to the enrolled dose group. In the dose escalation phase, no DLTs occurred; therefore, the MTD was not determined, and the highest dose, that is, 5.0×1011 VP/subject, was used as RED in the dose expansion phase for a total of 20 weeks. Before use, this product was diluted to 1 mL with normal saline and injected into the tumor directly or under the guidance of ultrasonography or CT. Although intratumoral injection was the preferred route of drug administration in this study, the investigator was allowed to explore other administration routes, such as intravesical instillation or intraperitoneal administration, based on the subject’s condition.

    Study endpoints

    The primary endpoint was safety of YSCH-01 assessed by incidence and characteristics of adverse events (AEs)/serious AEs (SAEs) determined using the National Cancer Institute Common Terminology Criteria for Adverse Events V.5.0. The relationship of AEs to the investigational drug was assessed on a 5-point scale. During the dose escalation phase, viral shedding was initially tested in the first patient in each dose group, and if not detected, subsequent subjects in that dose group were exempted from the viral shedding test. Quantitative PCR was performed to determine the number of copies of YSCH-01 gDNA, and an adenovirus titer kit was used to assess the titer of YSCH-01.

    The secondary endpoints included PKs assessed by maximum plasma concentration (Cmax), time of maximum plasma drug concentration (Tmax), the area under the curve (AUC), mean retention time, apparent volume of distribution, the volume of distribution, total clearance, half-life (t1/2), trough concentration at steady state, peak concentration at steady state, average plasma concentration at steady state, area under the drug-time curve during the dosing interval (AUC0-tau), Tmax, accumulation ratio of Cmax, accumulation ratio of AUC0-tau, and volume of distribution at steady state, clearance at steady state and elimination phase t1/2, etc, immunogenicity assessed by anti-drug antibody and neutralizing antibody, preliminary efficacy assessed by objective response rate (ORR), disease control rate (DCR), duration of response, progression-free survival (PFS), and overall survival (OS). Efficacy evaluation was performed using the internationally recognized Response Evaluation Criteria in Solid Tumor V.1.1 (RECIST V.1.1)5 for initial assessment, staging, and efficacy evaluation, while Immune Response Evaluation Criteria in Solid Tumors (iRECIST) criteria6 was also adopted exploratively.

    Statistical analysis

    Statistical analysis was performed using SAS V.9.4, and the primary PK parameters for each subject were calculated using the non-compartmental models of WinNonlin (V.8.3). For measurement data, descriptive statistics, including mean, SD, median, maximum, and minimum (and also the geometric mean and coefficient of variation for PK parameters), were used; for enumeration or ranked data, descriptive statistics, including absolute frequency and relative frequency, were used.

    The following statistical analysis population sets were used:

    Full analysis set (FAS): Based on intent-to-treat, all subjects who were successfully enrolled and had at least one treatment record were included in the full analysis set of this study. The enrolled subjects may be caused to be excluded from the FAS by the following situations: for example, the main inclusion criteria are not met, the investigational drug has not been used, and there is no data after enrollment. Demographic data, baseline data, and efficacy indicators were statistically analyzed based on the FAS.

    Efficacy analysis set: Subjects in FAS who had completed at least one efficacy assessment.

    Safety set (SS): All subjects who have received at least one dose of treatment and have safety evaluation data following treatment were included. The safety population was primarily used for the analysis of safety data.

    Pharmacokinetics analysis set (PKS): All subjects who were enrolled and received at least one dose of the investigational drug and had data for post-dose PK evaluation constituted the PK analysis set of this study. In the PK analysis set, different PK parameters may include different numbers of subjects depending on the actual study completion.

    Results

    Study subjects

    Based on the electronic data capture transmitted as of November 16, 2023, a total of 18 subjects were screened, with 14 subjects actually enrolled in the study, including 9 subjects to the dose escalation phase and 5 subjects to the dose expansion phase. 9 subjects prematurely withdrew from the study, including 5 subjects from the dose escalation phase and 4 subjects from the dose expansion phase. 5 subjects completed the study as required by the protocol. Among the 14 enrolled subjects, one subject voluntarily withdrew from the study without receiving the investigational drug, and the other 13 subjects were all included in the FAS, SS, and PKS. In addition, 2 subjects among the 13 subjects enrolled in FAS withdrew early after administration and did not undergo efficacy evaluation, and were not included in EAS. Please see figure 1 and online supplemental file 2.

    Supplemental material

    Figure 1
    Figure 1

    Case-screening flowchart. EAS, efficacy analysis set; FAS, full analysis set; ICF, informed consent form; SS, safety set.

    Demographics

    Of the 13 subjects included in FAS to date, 4 (30.8%) subjects were men and 9 (69.2%) subjects were women. All 13 subjects were Han Chinese, and the average age was 61.08±9.72 years. Detailed demographic characteristics of each dose group are presented in table 1.

    View this table:
    Table 1

    Demographic characteristics of the enrolled subjects (full analysis set)

    Medical history

    Tumor types of the 13 subjects included in FAS were as follows: 5 (38.5%) subjects had lung cancer, 3 (23.1%) subjects had breast cancer, 3 (23.1%) subjects had melanoma, 1 (7.7%) subject had ovarian cancer, and 1 (7.7%) subject had head and neck cancer. The average course of the disease was 60.94±57.78 months. Other medical and treatment histories of the 13 subjects included in FAS were as follows: 13 (100%) subjects had prior surgery/procedures; 10 (76.9%) subjects had prior chemotherapy; 4 (30.8%) subjects had prior radiotherapy; 1 (7.7%) subject had prior interventional procedure including chemotherapy medication; 8 (61.5%) subjects had other tumor-related treatment history; and 10 (76.9%) subjects had other pre-existing and concomitant diseases (online supplemental file 3).

    Supplemental material

    Tolerability analysis

    For the dose escalation phase, three dose groups were established, that is, 5.0×109 dose group, 5.0×1010 dose group, and 5.0×1011 dose group. During the dose escalation phase, no subject experienced DLTs.

    PK results

    Overall, the content of recombinant L-IFN adenovirus genome (gDNA) and recombinant L-IFN protein (L-IFN) in blood showed no trend of significant intergroup changes. For each dose group of the dose escalation phase and the dose expansion phase, the PK parameters of recombinant L-IFN adenovirus genome and the plasma PK parameters of L-IFN protein in plasma are provided in online supplemental file 4 and online supplemental file 5.

    Supplemental material

    Supplemental material

    PDs analysis

    PD samples were collected from subjects during the dose escalation phase of this study to investigate the relationship between exposure and PD biomarkers. This periodic analysis only covered interleukin-6 (IL-6), interferon-gamma (IFN-γ), and natural killer (NK) cells (CD16+CD56+). No significant change was observed in IL-6, IFN-γ, and NK cells over the visit time point. Emax of IL-6 and IFN-γ increased with the increase of dose, and Emax of NK cell decreased with the increase of dose. The detailed results of each dose group are as follows:

    In the 5.0×109 dose group, the mean Emax of IL-6 was 12.12±11.82 pg/mL, and the median Tmax of IL-6 was 168.00 (6–168) hours; the mean Emax of IFN-γ was 1.42±0.39 pg/mL and the median Tmax of IFN-γ was 168.00 (24–168) hours; the mean Emax of NK cell was 455.00±175.36 pg/mL and the median Tmax of NK cell was 120.00 (72–168) hours. In the 5.0×1010 dose group, the mean Emax of IL-6 was 15.15±6.97 pg/mL and the median Tmax of IL-6 was 168.00 (72–168) hours; the mean Emax of IFN-γ was 3.02±1.27 pg/mL and the median Tmax of IFN-γ was 168.00 (24–168) hours; the mean Emax of NK cell was 300.00±203.68 pg/mL and the median Tmax of NK cell was 0.00 (0–6) hours. In the 5.0×1011 dose group, the mean Emax of IL-6 was 53.12±54.45 pg/mL, and the median Tmax of IL-6 was 6.00 (0–6) hours; the mean Emax of IFN-γ was 3.29±0.79 pg/mL and the median Tmax of IFN-γ was 24.00 (24–24) hours; the mean Emax of NK cell was 202.67±67.04 pg/mL and the median Tmax of NK cell was 0.00 (0–72) hours (see online supplemental file 4 for details).

    Efficacy analysis

    Overall response rate and disease control rate

    In the dose escalation phase (N=8), no complete response (CR) was observed, but 25.0% of patients demonstrated a partial response (PR) and 50.0% maintained stable disease (SD), and the ORR with its 95% CI was 25.0% (3.19% to 65.09%). In the dose expansion phase (N=3), no CR was observed, while 1 subject (33.3%) PR and 2 subjects (66.7%) had SD, and the ORR with its 95% CI was 33.3% (0.84% to 90.57%). The DCR with its 95% CI was 75.0% (34.91% to 96.81%) in the dose escalation phase and 100% (29.24% to 100.0%) in the dose expansion phase. Overall, for all 11 subjects in EAS, the ORR with its 95% CI was 27.3% (6.02% to 60.97%), and the DCR with its 95% CI was 81.8% (48.22% to 97.72%) (see table 2 for details).

    View this table:
    Table 2

    Best tumor response evaluation and analysis of objective response rate and disease control rate based on RECIST V.1.1 (efficacy analysis set)

    Progression-free survival

    For 13 subjects in the FAS, 5 subjects experienced endpoint events, and the mean PFS was 4.97 months. The Kaplan-Meier (K-M) curve of PFS is shown in figure 2. Please see online supplemental file 6 for detailed PFS data.

    Supplemental material

    Figure 2
    Figure 2

    Kaplan-Meier curve for progression-free survival (full analysis set). PFS, progression-free survival; VP, viral particles.

    Overall survival

    Based on the current data, three subjects in this study died, including two subjects in the 5.0×109 dose group and one subject in the 5.0×1010 dose group of the dose escalation phase. The rest of the subjects did not experience endpoint events and were censored. The median OS was 8.62 months (95% CI: 4.97 to NA) in the 5.0×109 dose group and 8.62 months for the dose escalation phase and dose expansion phase. The K-M curve of OS is shown in figure 3. Please see online supplemental file 6 for detailed OS data.

    Figure 3
    Figure 3

    K-M curve for overall survival (FAS). FAS, full analysis set; KM, Kaplan-Meier; OS, overall survival; VP, viral particles.

    Analysis of changes in diameters of target lesions

    During the dose escalation phase, a tendency of decrease in the sum of diameters of target lesions compared with the baseline was observed in two out of three subjects in the 5.0×109 dose group; the best response for them was SD and PR. A tendency of decrease in the sum of diameters of target lesions compared with the baseline was observed in one of three of the subjects in the 5.0×1010 dose group, and the best response for the subject was PR. A tendency of decrease in the sum of diameters of target lesions compared with the baseline was observed in one of two subjects in the 5.0×1011 dose group, and the best response for the subject was SD During the dose expansion phase, a tendency of decrease in the sum of diameters of target lesions compared with the baseline was observed in two out of three subjects, and the best response for them was SD and PR (refer to online supplemental file 7 for details).

    Supplemental material

    Safety evaluation

    There were 13 subjects included in the SS. A total of 9 (100%, 9/9) subjects experienced 76 AEs in the dose escalation phase. The incidences of AEs in 5.0×109, 5.0×1010, and 5.0×1011 dose groups were 100%. A total of 8 (88.9%, 8/9) subjects experienced 66 adverse drug reactions (ADRs) with ADR incidences of 66.7% in the 5.0×109 dose group and 100% in both the 5.0×1010 and 5.0×1011 dose groups. No AEs/ADRs leading to death occurred. Among the 4 subjects enrolled in the dose expansion phase, a total of 43 AEs occurred in 3 (75.0%, 3/4) subjects. A total of 41 ADRs occurred in 3 (75.0%, 3/4) subjects. The incidences of AE/ADR were 75.0% in all dose groups. In the dose expansion phase, no ≥Grade 3 AEs/ADRs, SAEs/serious ADRs, AEs/ADRs leading to death occurred. The overall incidence of AEs was 92.3% (12/13), the overall incidence of ADRs was 84.6% (11/13), the overall incidences of >Grade 3 AEs was 7.7% (1/13), and no AEs/ADRs leading to death occurred (see table 3 for details).

    View this table:
    Table 3

    Adverse events (safety set)

    The most common AEs (incidence >20%) classified by system organ class (SOC) were general disorders and administration site conditions (76.9%), gastrointestinal disorders (61.5%), metabolism and nutrition disorders (38.5%), respiratory, thoracic, and mediastinal disorders (38.5%), skin and subcutaneous tissue disorders (23.1%), and nervous system disorders (23.1%), and classified by preferred term (PT) were fever (69.2%), nausea (30.8%), vomiting (30.8%), and hypophagia (23.1%) (table 4). The most common ADRs (incidence >20%) classified by SOC included general disorders and administration site conditions (76.9%), gastrointestinal disorders (53.8%), metabolism and nutrition disorders (38.5%), respiratory, thoracic, and mediastinal disorders (38.5%), skin and subcutaneous tissue disorders (23.1%), and nervous system disorders (23.1%), and classified by PT included fever (69.2%), vomiting (30.8%), nausea (23.1%), and hypophagia (23.1%) (table 5). Refer to online supplemental file 8 for the data on the most common treatment-emergent adverse events (TEAEs) and ADRs characterized by grades.

    Supplemental material

    View this table:
    Table 4

    Adverse events by system organ class (safety set)

    View this table:
    Table 5

    Adverse drug reactions by system organ class (safety set)

    A total of 5 subjects (38.5%, 5/13) had 24 AEs “definitely related” to the investigational drug during the dose escalation and dose expansion phases, 4 subjects (30.8%, 4/13) had 23 AEs “probably related” to the investigational drug, 11 subjects (84.6%, 11/13) had 60 AEs “possibly related” to the investigational drug, 3 subjects (23.1%, 3/13) had experienced 7 AEs “unlikely unrelated” to the investigational drug, while 2 subjects (15.4%, 2/13) subjects had 5 AEs “definitely not related” to the investigational drug. There were 10 subjects (76.9%, 10/13) with 71 AEs outcomes indicating resolved, 6 subjects (46.2%, 6/13) with 39 AEs outcomes indicating resolving, 2 subjects (15.4%, 2/13) with 3 AEs outcomes indicating stable, 1 subject (7.7%, 1/13) with 1 AE outcome indicating aggravated, and 3 subjects (23.1%, 3/13) with 4 AEs outcomes indicating stable.

    Viral shedding test

    Quantitative PCR was performed to determine the number of copies of YSCH-01 gDNA, and the adenovirus titer kit was used to assess the titer of YSCH-01. Tests performed in the first subject at each dose level (5×109 VP, 5×1010 VP, 5×1011 VP) revealed that although low enrichment level of YSCH-01 gDNA (number of copies) was detected in the injection site at 1-hour post-dose and in the nasopharyngeal fluid on 1-day post-dose in the low-dose group, no live virus was detected in these samples. No live virus was detected in samples of feces, urine, nasopharyngeal fluid, and injection site collected continuously after administration. In addition, no adenovirus-related infection was reported by close contact of subjects and healthcare personnel.

    Discussion

    OV therapy has seen rapid advancements due to its relatively safe mode of action and its potential to achieve enhanced efficacy compared with currently available treatment options. Currently, four OV products have been approved for marketing: RIGVIR,7 approved in Latvia in 2004 for the treatment of melanoma; Oncorine,8 approved by the China National Medical Products Administration in 2005 for the treatment of nasopharyngeal cancer in combination with chemotherapy; T-Vec,9 approved by the US Food and Drug Administration (FDA) in 2015 for the treatment of unresectable recurrent malignant melanoma, being the sole OV therapy approved by the FDA; and Delytact,10 which received conditional and time‐limited marketing approval from the Ministry of Health, Labour and Welfare in June 2021, being the first-in-class approved OV therapy for cephalic glioma. OVs introduce new prospects into the field of tumor treatment.

    According to the development plan, YSCH-01 uses a broad-spectrum antitumor oncolytic adenovirus vector whose possible indications are not limited to specific tumor types. Preclinical PDs studies have also shown that YSCH-01 has excellent efficacy in mouse xenotransplantation models of a variety of tumors, including triple-negative breast cancer (TNBC), cervical cancer, glioblastoma, bladder cancer, head and neck squamous cell carcinoma, melanoma, and non-small cell lung cancer, so these tumor types can be used as clinical indications for YSCH-01. The results of the safety pharmacology showed that only transient cardiovascular changes were observed when YSCH-01 was administered intravenously or subcutaneously at high doses, indicating that YSCH-01 is generally safe. The results of toxicological studies under Good Laboratory Practice (GLP) conditions showed that in the Syrian hamster model, the STD10 for YSCH-01 was 1.0×1011 VP/animal (6.7×1011 VP/kg）via intratumoral (IT) injection and >2.0×1011 VP/kg via intravenous injection. In the rhesus monkey model, the HNSTD of YSCH-01 was 1.8×1011 VP/kg via intravenous injection and 4.5×1011 VP/kg via subcutaneous injection. This was a single-center/multicenter, open-label, dose escalation, and dose expansion clinical study in patients with recurrent/refractory advanced solid tumors to evaluate the safety/tolerability, PK/PD, and preliminary efficacy of YSCH-01 injection in the treatment of recurrent/refractory solid tumors. Based on the current data, a total of 18 subjects were screened for this study. This study consisted of dose escalation and dose expansion phases. During the dose escalation phase, no subject experienced DLTs. PK profile analysis showed no significant tendency in the content of recombinant L-IFN adenovirus genome (gDNA) and L-IFN protein (L-IFN) in the blood. The PDs analysis revealed no significant changes in IL-6, IFN-γ, and NK cells over the visit time point.

    The efficacy analysis showed that the best ORR was 27.3%, the best DCR was 81.8%, the median PFS was 4.97 months, and the median OS was 8.62 months, suggesting that YSCH-01 has a good efficacy against advanced solid tumors. The efficacy data in this study is superior to other Phase I studies of adenovirus-based OV therapies against solid tumors. A study by Ranki et al11 showed that Oncos-102 had a DCR of 40% and an median PFS of 2.9 months when administered intratumorally to subjects with advanced solid tumors. Another study by Garcia-Carbonero et al12 showed that VCN-01 had a DCR of only 25%, which is significantly lower than the 80% reported in this study.

    YSCH-01 is an oncolytic adenovirus product developed based on the CTGVT strategy, which carries the multifunctional therapeutic gene L-IFN.13 14 Theoretically, the product has an excellent efficacy and safety profile. Specifically, the adenovirus vector was first designed using a unique dual regulation strategy targeting replication (ie, replacing its wild-type E1A promoter with a truncated optimized survivin promoter and deleting the 24 bp nucleic acid sequence in the CR2 region of the E1A gene) to improve its ability to target tumor cells and its safety to normal cells.15 16 When the oncolytic adenovirus vector specifically replicates in large numbers in tumors, the L-IFN gene it carries will also be replicated and expressed in large numbers to exert antitumor effects together with the viral vector.13 YSCH-01 has undergone comprehensive non-clinical studies, which have suggested that YSCH-01 exerts its antitumor activity in the following ways: replicating in large numbers in tumor cells to lyse them, inducing apoptosis and autophagy of tumor cells, regulating the immune microenvironment in tumors, such as promoting immune cell infiltration, activating NK and CD8+T cell function, and increasing cytokine secretion, up-regulating the expression of MHC-I protein on the surface of tumor cells to promote the presentation of tumor antigen, and inhibiting angiogenesis in tumors.17 18

    This study has shown that during the dose escalation phase, no subject experienced DLTs. Overall, a total of 119 AEs occurred in 12 subjects, with an overall incidence of 92.3%. A total of 107 ADRs were reported in 11 subjects, with an overall incidence of 84.6%. The overall incidence of >Grade 3 AEs/ADRs was 7.7%, and there were no AEs/ADRs leading to death. It is also important to note that only 38.5% of AEs were “definitely related” and 30.8% of AEs were “probably related” to the investigational drug. By the data cut-off date, 71 AEs had completely resolved. This shows that YSCH-01 injections, when administered intratumorally to patients with advanced solid tumors, are safe and tolerable. The safety data of YSCH-01 reported in this study is comparable to other similar drugs.11 12 19 20

    In this study, the most common AEs (incidence >20%) classified by SOC were general disorders and administration site conditions (76.9%), gastrointestinal disorders (61.5%), respiratory, thoracic, and mediastinal disorders (38.5%), metabolism and nutrition disorders (38.5%), skin and subcutaneous tissue disorders (23.1%), nervous system disorders (23.1%), and infections and infestations (23.1%), and by PT were fever (69.2%), nausea (30.8%), and vomiting (30.8%). Fever is a common AE reported in studies of other OVs.21–23 Fever is a common response to infections and is often mediated by the release of pro-inflammatory cytokines, such as IL-1, IL-6, and tumor necrosis factor-alpha, as part of the body’s defense against pathogens. However, we found that fever was self-limiting in all subjects. Nausea and vomiting, on the other hand, are common in patients with advanced cancer and not necessarily related to the treatment. The etiology of these symptoms is multifaceted. Another important AE in this study, which was definitely related to the study drug, was injection site pain. YSCH-01 was administered intratumorally. The injection site pain can be attributed to the direct inflammatory response elicited by the drug administration. The size and location of the tumor being treated may influence the extent of injection site pain. Larger tumors or those located in sensitive areas may cause more discomfort. Immunogenicity analysis showed no correlation between anti-adenovirus antibody titers and therapeutic effects/ADRs, which was similar to the results of clinical studies of drugs of the same class listed in China and abroad.24

    There are some limitations to this study. First, this was a single-center and investigator-initiated trial, and the findings may be subject to center-specific biases. Second, the small sample size and the lack of diversity (all subjects being Han Chinese) among participants limit the ability to apply these results universally; therefore, further multicenter studies with large sample sizes and more diverse populations are required to confirm our findings.

    Conclusions

    This study showed that the best ORR was 27.3%, the best DCR was 81.8%, the median PFS was 4.97 months, and the median OS was 8.62 months, showing preliminary efficacy of YSCH-01 in patients with advanced solid tumors. In addition, YSCH-01 was well tolerated by subjects as no DLTs occurred during the dose escalation phase, and the overall incidence of AEs was 92.3% and the overall incidence of ADRs was 84.6%, while no AEs/ADRs leading to death occurred. In conclusion, the investigational drug was safe and well tolerated and exhibited preliminary efficacy in patients with solid tumors, supporting further investigation to evaluate its efficacy and safety.

    Data availability statement

    Data are available upon reasonable request. The data and materials that supported the findings in this research are available upon reasonable request to the corresponding author.

    Ethics statements

    Patient consent for publication

    Ethics approval

    This study was approved by the Ethics Committee of Fengxian Central Hospital, Shanghai on October 15, 2021, with the approval number of 221-KY-16-02. Participants gave informed consent to participate in the study before taking part.

    Acknowledgments

    We thank the entire staff of the hospital Ethics Committee and the GCP Office for their support.

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    Supplementary materials

    Footnotes

    • YH, XH and XL contributed equally.

    • Contributors FL and RZ contributed to the conception, design, data acquisition, and interpretation; performed all statistical analyses, drafted, and critically revised the manuscript. YH, XH, XL, HL, ML, JT, YS, HKR, YL, WZ, X-pC, Y-yY, K-jZ, and X-lF contributed to the data acquisition and analysis. HKR, K-jZ, and RL drafted and critically revised the manuscript. FL accepts full responsibility for the finished work and/or the conduct of the study, had access to the data, and controlled the decision to publish.

    • Funding This work was supported by investigator-initiated trial (IIT) project on Hospital-Enterprise Cooperation (Grant No. 2021-KY-16-03); Academician Expert Workstation Grants (No. 19R1002275468, 20R9004076411, 21R4007547098, S182023110190129357) in Shanghai Yuansong Biotechnology Co., Shanghai science and technology support project on biomedicine in the action plan of Science and Technology Innovation (Grant No. 19431904200).

    • Competing interests K-jZ and X-lF hold an ownership interest (including patents of YSCH‑01) in Yuansong Biotechnology Limited Company. Other authors report no conflict of interest.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.