A Retrospective Study of Anlotinib Combined with Anti-PD-1 Inhibitors in the 2nd or Later-Line Treatment of Advanced Solid Tumors.

Objective: To investigate the clinical efficacy and safety of anlotinib combined with anti-PD-1 inhibitors in the 2nd or later-line treatment of advanced solid tumors. Patients and Methods: A total of 63 patients with advanced solid tumors who had failed or could not endure the adverse reactions after receiving first-line or more systematic treatment in the Second Affiliated Hospital of Harbin Medical University from March 2019 to April 2023 were treated with anlotinib Hydrochloride capsule combined with anti-PD-1 inhibitors. The efficacy and adverse reactions were evaluated according to RECIST1.1 and NCICTC4.0 standards. Results: The percentage of overall response rate of 63 patients during the combination administration indicated that complete response was 1.6% (n=1), partial response was 23.8% (n=15), stable disease was 39.7% (n=25) and progressive disease was 34.9% (n=22), yielding objective response rate (ORR) of 25.4% and disease control rate (DCR) of 65.1%. Furthermore, the median PFS of 63 patients with advanced solid tumors was 7 months and the median OS was not reached, and the median follow-up time is 4.5 months. In subgroup analysis, there was no significant difference in PFS between first-line, second-line, third-line and above (p=0.631); there was no significant difference in PFS between PD-1 positive patients and PD-1 negative patients (p=0.094); there was no significant difference in PFS between patients who had previously used anti-PD-1 inhibitors and patients who had not used before (p=0.204). The most common adverse reactions were hypertension, hand-foot syndrome, and fatigue, with an incidence of 28.4% (18/63), 25.6% (14/63), and 25.6% (14/63), respectively. Most of the adverse reactions were grade 1-2, and there were no grade 4 adverse reactions. Conclusion: Anlotinib combined with anti-PD-1 inhibitors demonstrated promising efficacy and tolerable safety for patients with advanced solid tumors in the 2nd or later-line treatment.

Synergistic efficacy of PI3Kδ inhibitor with anti-PD-1 mAbs in immune-humanized PDX model of endocrine resistance hormone receptor-positive advanced breast cancer.

Purpose: Endocrine resistance hormone receptor-positive (HR+) advanced breast cancer (ABC) is generally insensitive to immunecheckpoint inhibitors (ICIs). This study sought to determine whether PI3Kδ inhibitor could enhance the sensitivity of endocrine resistance HR + advanced BC to ICIs by reducing immune evasion. Methods: Patient-derived HR + ABC xenografts were implanted into immune-humanized NSG mice and subsequently treated with YY20394 (PI3Kδ inhibitor) and camrelizumab. The mice were monitored for tumor progression, biochemical blood indicators, and peripheral blood T-cell subsets. The xenografted tumors were collected at the end of the treatment cycle and subjected to HE staining, immunohistochemistry and protein phosphorylation analysis. Besides, the xenografted tumors were also used to isolate primary breast cancer cells (BCCs) and regulatory T-cells (Tregs), which were subsequently used to evaluate drug sensitivity in vitro. Results: The humanized PDX model showed a favorable initial treatment response to camrelizumab combined with YY20394 and manageable toxicity. YY20394 plus camrelizumab showed a strong inhibitory effect on HR + BC in vivo mediated by suppression of Treg activity and an increased proportion of CD8+ T cells. Mice bearing tumors treated with YY20394 and camrelizumab had less invasion, mitotic figures, and ki67 expression, while having higher IL-12 expression compared with other groups. Mechanistically, YY20394 only effectively inhibited the PI3K pathway and proliferation activity in Tregs but not in BCCs. Conclusion: Our study suggests PI3Kδ inhibitor could the enhance the efficacy of ICIs in HR + BC PDX models by combating immune suppression and provides a feasible approach that may overcome the resistance of ICIs in HR + BC patients.

Postoperative pathological complete response in a patient with PD­L1­negative stage IIIB lung squamous cell carcinoma following neoadjuvant tislelizumab treatment combined with chemotherapy: A case report and literature review.

The utilization of immune checkpoint inhibitors in oncological treatment has increased in recent years. The therapeutic strategy of targeting the programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) pathway has altered the management of advanced non-small cell lung carcinoma (NSCLC). Tislelizumab, a novel anti-PD-1 monoclonal antibody developed in China, has demonstrated efficacy in treating advanced NSCLC. However, its potential role as a neoadjuvant therapy for locally advanced NSCLC has not been definitively established. Current guidelines do not specify which patient populations may gain the most benefit from neoadjuvant immunotherapy coupled with chemotherapy, nor do they indicate the optimal timing, dose or duration of adjuvant maintenance therapy post-NSCLC surgery. Similarly, data concerning the safety and practicability of surgical resection following neoadjuvant tislelizumab treatment for NSCLC remain limited. The present study describes the case of a patient diagnosed with stage IIIB NSCLC, which was initially deemed unresectable. A preoperative biopsy of the tumor mass revealed squamous cell carcinoma and a negative PD-L1 gene test. Notably, after two cycles of neoadjuvant tislelizumab treatment coupled with chemotherapy, the tumor exhibited marked shrinkage. This permitted the patient to undergo thoracoscopic radical lung cancer resection, which resulted in a pathological complete response. Postoperative pathology identified a large infiltration of lymphoplasmacytic cells and foamy histiocytes. The patient experienced grade 2 myelosuppression, a condition that was successfully addressed with the administration of recombinant human granulocyte colony-stimulating factor. The present case indicates the safety and feasibility of neoadjuvant immunotherapy integrated with chemotherapy for patients with locally advanced, PD-L1-negative NSCLC prior to surgical intervention. Moreover, the case suggests the potential of this therapeutic combination to alter the tumor microenvironment. However, the generalization of these findings necessitates further validation through randomized multicenter trials.

Advanced thymic lymphoepithelioma-like carcinoma with bone marrow metastases treated by immunotherapy combined with antiangiogenesis therapy: a case report.

Thymic lymphoepithelioma-like carcinoma (LELC) is a rare primary malignant neoplasm originating from the thymus. Thymic LELC diagnosis is often terminal when diagnosed, some patients have lost the opportunity for surgery. Platinum- and anthracycline-based systemic chemotherapy are the first-line treatment plan; however, there is no clear consensus on therapy when first-line treatment fails because of the lack of cases of advanced thymic LELC. Here was a rare case of advanced thymic LELC with bone marrow metastasis at relapse, which is reported in a patient who responded well to toripalimab combined with anlotinib therapy. The treatment showed tolerable toxicity with good antitumor activity in the patient. As far as we know, this is the first case that the combination of toripalimab with anlotinib is effective in controlling advanced thymic LELC with bone marrow metastasis. The case reports represent an essential means by which an effective therapy for advanced thymic LELC may not be practical given the low frequency of a thymic LELC with multiple metastases.