The efficacy of subsequent therapy after failure of anti-PD-1 antibody in metastatic renal cell carcinoma.

Background: The optional regimens of subsequent therapy after failure of anti-programmed cell death protein-1 (PD-1) antibody in metastatic renal cell carcinoma (mRCC) remain to be explored. There are reports of the efficacy of single-agent vascular endothelial growth factor receptor tyrosine kinase inhibitor (VEGFR-TKI) in patients with mRCC after failure of anti-PD-1 antibody therapy. However, it is not clear whether it is beneficial for patients to receive anti-PD-1 antibody as post-progression treatment. It has great significance to explore whether continuous application of anti-PD-1 antibody is beneficial for patients with mRCC whose diseases progressed to the state of pre-anti-PD-1 therapy. The purposes of this study are to explore the efficacy and safety of subsequent treatment on whether to continue using anti-PD-1 antibody therapy for patients who have progressive mRCC after prior treatment with anti-PD-1 antibody. Methods: The clinical data of patients with mRCC from the Department of Immunotherapy in the Affiliated Cancer Hospital of Zhengzhou University and Henan Cancer Hospital from February 1, 2019 to December 31, 2021 were analyzed retrospectively. The primary endpoints were the objective response rate (ORR) and progression-free survival (PFS). The ORR and disease control rate (DCR) were estimated with Fisher's exact test. PFS and overall survival (OS) were assessed using the Kaplan-Meier method and log-rank tests. The associations between potential prognostic variables and PFS were evaluated with univariate and multivariate Cox regression analyses. A P value of less than or equal to 0.05 was deemed as statistically significant. Results: A total of 35 patients were included in this study, during which 19 received VEGFR-TKI monotherapy and 16 received the VEGFR-TKI plus anti-PD-1 antibody therapy. Until the last follow-up on June 30, 2022, 19 patients experienced progressive disease (PD), five were in remission, and 11 kept stable disease (SD). After a median follow-up of 28.7 [95% confidence interval (CI): 17.0-35.6] months, the median PFS (mPFS) was 11.6 months for the VEGFR-TKI group and 9.1 months for the VEGFR-TKI plus anti-PD-1 antibody group [hazard ratio (HR) =0.81, 95% CI: 0.32-1.03, P=0.44]. Median OS (mOS) were 16.9 and 11.2 months respectively (HR =0.99, 95% CI: 0.44-2.27, P=0.90). The ORRs were 26.3% and 0% (P=0.049), and the DCRs were 47.4% and 43.8% (P=0.55) respectively. Treatment-related adverse events (TRAEs) occurred in 14 patients (73.7%) in the VEGFR-TKI group and 14 patients (87.5%) in the VEGFR-TKI plus anti-PD-1 antibody group (P=0.42); grade 3/4 TRAEs occurred in two patients (10.5%) and six patients (37.5%) respectively (P=0.11). Conclusions: VEGFR-TKI monotherapy is an efficacious regimen for patients with mRCC whose diseases progressed on previous anti-PD-1 antibody therapy, and continuous anti-PD-1 therapy after failure of anti-PD-1 antibody could not provide additional clinical benefit but increased the incidence of TRAEs.

Neoadjuvant chemoimmunotherapy in locally advanced gastric or gastroesophageal junction adenocarcinoma.

Patients suffering from locally advanced gastric or gastroesophageal junction adenocarcinoma often face a high postoperative recurrence rate. Despite aggressive treatment, less than 50% survive beyond five years. Ongoing clinical studies are exploring ways to prolong patient survival, revealing that perioperative chemotherapy can extend both the period of recurrence-free survival and overall survival for this group of patients. Currently, combining chemotherapy and immune checkpoint inhibitors has become a critical treatment approach for advanced gastric or gastroesophageal junction adenocarcinoma. However, the effectiveness of this approach in locally advanced patients remains unverified. This article delves into the latest research concerning the use of perioperative chemotherapy coupled with immune checkpoint inhibitors in locally advanced gastric or gastroesophageal junction adenocarcinoma treatment, and highlights prospective challenges and discusses how to best identify patients who may benefit from combined chemotherapy and immune checkpoint inhibitor therapy.

The inter-link of ageing, cancer and immunity: findings from real-world retrospective study.

BACKGROUND: Although the concept of declined immune function associated with cancer has been accepted extensively, real-world clinical studies focusing on analysis of the peripheral blood immune changes underlying ageing, immunity and cancer are scarce. METHODS: In this case-control study, we retrospectively analysed 1375 cancer patients and enrolled 275 age and gender matched healthy individuals. Flow cytometry was conducted to assess the immune changes. Further analysis was examined by SPSS 17.0 and GraphPad Prism 9 software. RESULTS: Cancer patients showed obviously decreased CD3+ T, CD3+CD4+ Th, CD3+CD8+ CTL, CD19+ B, CD16+CD56+ NK cell counts and lower percentage of PD-1 (programmed cell death protein-1, PD-1) positive cells than healthy control (P < 0.0001). For cancer patients, the reference range of circulating percentage of PD-1+CD45+ cells, PD-1+CD3+ T cells, PD-1+CD3+CD4+ Th cells and PD-1+CD3+CD8+ CTL (Cytotoxic T Lymphocyte, CTL) were 11.2% (95% CI 10.8%-11.6%), 15.5% (95% CI 14.7%-16.0%), 15.4% (95% CI 14.9%-16.0%) and 14.5% (95% CI 14.0%-15.5%), respectively. Moreover, the reduction of CD3+ T, CD3+CD4+ Th, CD3+CD8+ CTL, CD19+ B cell counts accompanied with age and stage advancing (P < 0.05). CD16+CD56+ NK cells decreased with stage, but elevated in aged and male cancer patients (P < 0.05). Additionally, the percentage of PD-1 positive cells varied across cancer types, raised with age and stage. Head and neck, pancreatic, gynaecological and lung demonstrated a higher level of the percentage of PD-1 positive cells than melanoma, prostate, and breast cancer (P < 0.05). CONCLUSIONS: This study provides the reference range of the percentage of PD-1 positive cells on peripheral blood, confirms the decreased immune cells and a series of immune changes accompanying with cancer, expands our real world evidence to better understand the interactions of ageing, cancer and immunity. Moreover, the circulating percentage of PD-1 positive cells shows similar tumor type distribution with tumor mutational burden (TMB), supports that it maybe a potential predictive biomarker for immune checkpoint inhibitor therapy.

Immune-related pneumonitis requiring low-dose prednisone maintenance in one patient with durable complete response.

INTRODUCTION: Immune-related pneumonitis is an uncommon but potentially life-threatening adverse event associated with anti-programmed cell death protein-1 therapy, and has a higher recurrence rate than that of other pneumonitis. Glucocorticoids are the first treatment of choice for patients with immune-related pneumonitis over grade 1. Given the toxicity associated with glucocorticoids, they should be withdrawn gradually as soon as pneumonitis is controlled. However, low-dose glucocorticoids are maintained in some patients to prevent immune-related pneumonitis. CASE REPORT: We report a rare case of a patient with Hodgkin lymphoma who developed grade 2 immune-related pneumonitis, requiring long-term low-dose glucocorticoid maintenance therapy, during which pneumonitis disappeared, and complete response was achieved. MANAGEMENT AND OUTCOME: Tislelizumab treatment was stopped tentatively, and the patient was given prednisone at an initiating dose of 1 mg/kg/d. The cough symptoms were relieved significantly, and pneumonitis was reduced. The prednisone gradually dwindled, but the immune-related pneumonitis was recurrent, requiring prednisone 10 mg daily maintenance therapy. Subsequently, prednisone and tislelizumab were administered simultaneously, and at present, pneumonitis disappeared and the lesions are in complete remission. DISCUSSION: Low-dose glucocorticoids might play an important role in controlling the recurrence and development of immune-related pneumonitis. The dose and course of glucocorticoid in immune-related pneumonitis patients should be individualized to minimize the toxicity of glucocorticoid.

Sintilimab maintenance therapy post first-line cytokine-induced killer cells plus chemotherapy for extensive-stage small cell lung cancer.

Despite recent progress in treating advanced non-small cell lung cancer, clinical intervention in extensive-stage small-cell lung cancer (ES-SCLC) remains stagnant. The purpose of this study was to evaluate the clinical efficacy of cytokine-induced killer (CIK) cells combined with cytotoxic chemotherapy, followed by anti-programmed death 1 antibody (sintilimab) maintenance, in ES-SCLC patients. To explore a new method for safe treatment of ES-SCLC patients, thirteen ES-SCLC patients were enrolled between June 2019 and December 2021. All patients received first-line chemotherapy (etoposide plus platinum) combined with CIK cell therapy. Patients who reached a stable disease state or responded well to treatment received sintilimab maintenance treatment. The primary objective of this study was to determine the median overall survival (OS); the secondary objective was to assess the objective response rate (ORR), progression-free survival 1 and 2 (PFS1 was defined as the duration from the signing of informed consent to the date of tumor progression, or death, or the last follow-up. PFS2 was defined as the duration from the first day of sintilimab treatment to the date of tumor progression, death, or the last follow-up.), and adverse reactions. At a 24.1-month follow-up, the median OS was 11.8 (95% confidence interval [CI]: 10.6-13.0) months, median PFS1 was 5.5 (95% CI: 5.0-6.0) months, and the median PFS2 was 2.3 (95% CI: 0.5-4.1) months. The ORR was 76.9% (10/13), the disease control rate was 100% (13/13), and the 20-month survival rate was 41.7%. Eight participants exhibited grade 3 or 4 adverse events after combination therapy. During maintenance treatment with sintilimab, level 3 adverse events occurred in 1 patient (1/9). In conclusion, adding CIK cells to standard chemotherapy regimens, followed by maintenance therapy with sintilimab, may represent a new safe and effective treatment strategy. Clinical trial registration: ClinicalTrials.gov (NCT03983759).

Complete remission of ovarian clear cell carcinoma achieved after pseudoprogression during PD-1 inhibitor therapy.

Background: Ovarian clear cell carcinoma (OCCC), which is resistant to traditional treatment, has a poor prognosis. Immune checkpoint inhibitors (ICIs) have been emerged in the past decade and are now widely used in clinics. However, OCCC reportedly responds poorly to ICIs, and ICI monotherapy is rarely used for patients with OCCC. Methodology & Results: We report the case of a patient with refractory OCCC who received an ICI (nivolumab) monotherapy treatment and achieved a complete response despite the occurrence of pseudoprogression. Nivolumab was discontinued after 2 years, and the patient remained in complete remission more than a year after treatment withdrawal. Conclusion: This is the first report of complete remission being achieved in a case of refractory OCCC after pseudoprogression during nivolumab monotherapy.

The Sequence of Chemotherapy and Toripalimab Might Influence the Efficacy of Neoadjuvant Chemoimmunotherapy in Locally Advanced Esophageal Squamous Cell Cancer-A Phase II Study.

Background: There is no standard neoadjuvant therapy for locally advanced esophageal cancer in China. The role of neoadjuvant chemotherapy plus immunotherapy for locally advanced esophageal cancer is still being explored. Methods: This open-label, randomized phase II study was conducted at a single center between July 2019 and September 2020; 30 patients with locally advanced esophageal squamous cell carcinoma (ESCC) (T3, T4, or lymph-node positive) were enrolled. Patients were randomized according to the enrollment order at a 1:1 ratio to receive chemotherapy on day 1 and toripalimab on day 3 (experimental group) or chemotherapy and toripalimab on day 1 (control group). The chemotherapeutic regimen was paclitaxel and cisplatin. Surgery was performed 4 to 6 weeks after the second cycle of chemoimmunotherapy. The primary endpoint was pathological complete response (pCR) rate, and the secondary endpoint was safety and disease-free survival. Results: Thirty patients completed at least one cycle of chemoimmunotherapy; 11 in the experimental group and 13 in the control group received surgery. R0 resection was performed in all these 24 patients. Four patients (36%) in the experimental group and one (7%) in the control group achieved pCR. The experimental group showed a statistically non-significant higher pCR rate (p = 0.079). PD-L1 combined positive score (CPS) examination was performed in 14 patients; one in the control group had a PD-L1 CPS of 10, and pCR was achieved; the remaining 13 all had ≤1, and 11 of the 13 patients received surgery in which two (in the experimental group) achieved pCR. Two patients endured ≥grade 3 adverse events, and one suffered from grade 3 immune-related enteritis after one cycle of chemoimmunotherapy and dropped off the study. Another patient died from severe pulmonary infection and troponin elevation after surgery. Conclusions: Although the primary endpoint was not met, the initial results of this study showed that delaying toripalimab to day 3 in chemoimmunotherapy might achieve a higher pCR rate than that on the same day, and further large-sample clinical trials are needed to verify this. Clinical Trial Registration: ClinicalTrials.gov, identifier NCT03985670.

Case Report: Afatinib-Induced Interstitial Pneumonia: Experiences and Lessons From Two Patients.

Background: Afatinib has shown good efficacy in patients harboring uncommon EGFR mutations, but the incidence of afatinib-induced interstitial pneumonia should be alert as its rapid progression. Here, we report two cases of interstitial pneumonia during afatinib treatment. Case presentation: The first case was of a 58-year-old male with advanced lung adenocarcinoma (cT4bN3M1b) with exon 18 G719X and exon 20 S781I EGFR mutations and received afatinib therapy. After 68 days of therapy, he developed shortness of breath and fever. Drug-induced pneumonia was not diagnosed timely, the patient received empirical antibiotics and low-dose glucocorticoids. The pulmonary inflammation rapidly progressed and the patient died 15 days after symptom onset. The second case was of a 57-year-old man with stage IV (cT3N3M1b) lung adenocarcinoma with exon 21 L861Q EGFR mutation. He received afatinib as second-line therapy. Fever and shortness of breath occurred 22 days after afatinib therapy, he received empirical antibiotic therapy. Five days later, CT showed aggravated pulmonary inflammation, and afatinib-induced interstitial pneumonia was diagnosed. He received glucocorticoid therapy, and the pneumonia quickly improved. Conclusion: Although the incidence of EGFR-TKI-associated pneumonia is uncommon, high vigilance for drug-induced interstitial pneumonia is necessary during treatment. Early diagnosis and early glucocorticoid therapy could reverse lung injury.

T Cells Expanded from PD-1+ Peripheral Blood Lymphocytes Share More Clones with Paired Tumor-Infiltrating Lymphocytes.

Both tumor-infiltrating lymphocytes (TIL) and PD-1+ peripheral blood lymphocytes (PBL) are enriched for tumor-reactive clones recognizing known and unknown tumor antigens. However, the relationship between the T-cell receptor-ß (TCRß) repertoires of the TILs and T cells expanded from paired PD-1+ PBLs, and whether T cells expanded from PD-1+ PBLs can be used to treat patients with cancer as TIL substitutes remain unclear. Here, we established a highly efficient protocol to prepare polyclonal T cells from PD-1+ PBLs. A functional T-cell assay and tetramer staining revealed that cells from PD-1+ PBLs were relatively enriched for tumor-reactive T cells. Furthermore, deep TCRß sequencing data revealed that an average of 11.29% (1.32%-29.06%; P = 0.015; n = 8) tumor-resident clonotypes were found in T cells expanded from paired PD-1+ PBLs, and the mean accumulated frequency of TIL clones found in T cells expanded from PD-1+ PBLs was 35.11% (7.23%-78.02%; P = 0.017; n = 8). Moreover, treatment of four patients, who failed multiline therapy and developed acquired resistance to anti-PD-1, with autologous T cells expanded from PD-1+ PBLs combined with anti-PD-1 antibody elicited objective responses from three of them. These results indicate that T cells expanded from PD-1+ PBLs share more clones with paired TILs and could be used to treat patients with cancer as TIL substitutes. SIGNIFICANCE: This study harnesses the tumor reactivity of PD-1+ PBLs, developing a method to expand T cells from these clones as a potential therapeutic strategy and TIL substitute in patients with cancer.See related commentary by Ladle, p. 1940.

High Complete Response Rate in Patients With Metastatic Renal Cell Carcinoma Receiving Autologous Cytokine-Induced Killer Cell Therapy Plus Anti-Programmed Death-1 Agent: A Single-Center Study.

Background and Objective: The results of the CheckMate 025 trial established the status of nivolumab in the second-line treatment of metastatic renal cell carcinoma (mRCC), with an objective response rate (ORR) of 25% and a complete response (CR) rate of 1%. Thus, the efficacy of anti-programmed death (PD)-1 antibodies in the second-line treatment of mRCC requires improvement. The purpose of this study was to explore the clinical efficacy and safety of anti-PD-1 agents combined with cytokine-induced killer (CIK) cell therapy for refractory mRCC. Patients and Methods: Patients with mRCC refractory to previous targeted therapy were included in this study. All patients received anti-PD-1 plus CIK cell therapy. The ORR and CR rate, progression-free survival (PFS), overall survival (OS), and safety were assessed. Results: CR was observed in seven of the 29 patients, and partial response was observed in five patients. The ORR was 41.4% and the median PFS was 15.0 months. Up to the last follow-up, 15 patients died with an average survival time of 37 months. Among the patients who achieved a CR, one experienced cerebellar metastasis 18.8 months after discontinuation, but achieved CR again after localized gamma knife and 1-month axitinib treatment. This regimen was tolerated well and there was no treatment-related death. Conclusions: Combination therapy with anti-PD-1 and CIK cell therapy is safe and effective in patients with mRCC refractory to previous targeted therapy. The high CR rate and long disease-free survival even after long-term discontinued therapy suggest that this combination treatment may represent a potential curative regimen for this type of malignancy.

Chemotherapy Reverses Anti-PD-1 Resistance in One Patient With Advanced Non-small Lung Cell Cancer.

Background: Programmed cell death protein 1(PD-1) blockade has become a standard second-line treatment option for patients with advanced non-small cell lung cancer (NSCLC) without a driver gene mutation. Previous clinical studies showed that the objective response rate (ORR) of PD-1 blockade as second-line treatment for patients with NSCLC was ~20%, and the median progression-free survival (PFS) was ~4 months, with most patients eventually developing a resistance to PD-1 blockade. Although the ORR to chemotherapy after PD-1 blockade resistance was relatively high, the survival time of patients could not be significantly prolonged. Clinical oncologists are unclear about which treatment regimen should be selected after PD-1 blockade failure. Here, we report about a patient with advanced NSCLC and initial PD-1 blockade resistance who was observed to have a rapid partial response (PR) following one dose of chemotherapy and subsequent PD-1 blockade treatment. Case presentation: A 70-year-old woman with a history of left lower lobe lung surgery in March 2018 (pathological stage T1N2M0, EGFR wild-type) presented to our hospital. After six cycles of adjuvant chemotherapy, multiple nodules in both the lungs developed, and were suspected to be metastatic lesions. After another 2 months, the nodules in both the lungs enlarged. From November 2018 to March 2019, the patient received six cycles of pembrolizumab, and computed tomography (CT) confirmed a progressive disease status. She was then managed with 260 mg/m2 albumin paclitaxel once every 3 weeks. Subsequently, chemotherapy was discontinued after one cycle owing to grade three neuromuscular toxicity. Follow-up CT revealed a stable disease in May 2019. She then received another six cycles of pembrolizumab, which resulted in a PR. Conclusion: Chemotherapy may play a role in reversing PD-1 blockade resistance. If failure of PD-1 blockade occurs at first, re-administration of PD-1 blockade may be implemented if first followed by several cycles of chemotherapy. Because there are few reports on the use of chemotherapy to reverse PD-1 resistance, it is necessary to conduct clinical studies with larger patient cohorts to investigate whether chemotherapy can reverse PD-1 blockade resistance.

Factors Influencing the Efficacy of Anti-PD-1 Therapy in Chinese Patients with Advanced Melanoma.

PURPOSE: Anti-PD-1 antibody improves the survival of patients with advanced melanoma. However, the efficacy and safety of anti-programmed death protein 1 (PD-1) antibody have not been fully elucidated in Chinese melanoma patients, who show high frequency of mucosal and acral melanoma subtypes; besides, the factors influencing the efficacy of anti-PD-1 antibody have not been evaluated broadly. PATIENTS AND METHODS: Patients with advanced melanoma treated with regimens containing anti-PD-1 antibody from June 2016 to January 2019 were evaluated. Baseline characteristics and blood parameters were assessed, and outcome and adverse events were evaluated according to different regimens. The Cox proportional hazards regression model was used for univariate and multivariate analyses. RESULTS: A total of 51 patients with advanced melanoma were included in this study. The overall objective response rate (ORR) was 17.6%, the disease control rate was 58.5%, and the median time to progression was 5.2 months. The ORR of patients with PD-1 blockade-based combination therapy, without liver metastases and higher level of C-reactive protein (CRP) before PD-1 blockade, is higher than that of those not. Univariate analysis based on clinical features showed that ECOG scores, liver metastasis, elevated lactate dehydrogenase (LDH), and CRP levels were the factors affecting time to progression (TTP). Multivariate analysis showed that elevated CRP before PD-1 blockade was an independent predictive factor for ORR of PD-1 blockade therapy (P=0.009), while only Eastern Cooperative Oncology Group (ECOG) score was an independent predictor for TTP (P=0.032). The treatment was well tolerated in these cohort patients, and there was no treatment-related death. CONCLUSION: Anti-PD-1 antibody-containing regimen was safe and effective in Chinese patients with advanced melanoma, and elevated CRP and ECOG score were independent factors predicting the efficacy of anti-PD-1 therapy.

Clinical effects of autologous cytokine-induced killer cell-based immunotherapy in the treatment of endometrial cancer: a case report and literature review.

Endometrial cancer is the most prevalent gynecological malignancy in the USA, and its treatment involves surgery, chemotherapy, and radiotherapy. Cytokine-induced killer (CIK) cell-based treatments have shown antitumor activity against several solid tumors. However, to the best of our knowledge, there are no reports yet of CIK immunotherapy in the treatment of endometrial cancer, and consequently, little is known about its efficacy and safety. Here, we report a case of an endometrial cancer patient receiving a combination treatment with CIK cells immunotherapy and chemotherapy. Assessment for clinical features was carried out after every two cycles of CIK immunotherapy and chemotherapy. No severe toxicity was observed after infusion of CIK cells. After 4 cycles of treatment, the patient achieved complete response and showed elevated Karnofsky Performance Status scores with an overall survival time of 13.6 months. The combination therapy improved the quality of life and prolonged patient survival time, which suggested that CIK cell therapy might be a potentially beneficial option for endometrial cancer.

Autologous cytokine-induced killer cell immunotherapy may improve overall survival in advanced malignant melanoma patients.

AIMS: Our study was conducted to explore the efficacy of autologous cytokine-induced killer (CIK) cells in patients with advanced malignant melanoma. Materials & Methods: Here we reviewed 113 stage IV malignant melanoma patients among which 68 patients received CIK cell immunotherapy alone, while 45 patients accepted CIK cell therapy combined with chemotherapy. Results: We found that the median survival time in CIK cell group was longer than the combined therapy group (21 vs 15 months, p = 0.07). In addition, serum hemoglobin level as well as monocyte proportion and lymphocyte count were associated with patients' survival time. CONCLUSIONS: These indicated that CIK cell immunotherapy might extend survival time in advanced malignant melanoma patients. Furthermore, serum hemoglobin level, monocyte proportion and lymphocyte count could be prognostic indicators for melanoma.