Intracavitary infusion of FOLactis Lactobacillus leads to disappearance of MPE in patient with advanced lung adenocarcinoma

Abstract

This case report presents the application of FOLactis, a lactic acid bacterium in situ vaccine, in the treatment of a lung adenocarcinoma patient who presented with malignant pleural effusion (MPE). An adult patient diagnosed with lung adenocarcinoma complicated by malignant pleural effusion (MPE) experienced favorable outcomes following the administration of intracavitary infusion of FOLactis, as conventional therapeutic approaches failed to yield satisfactory results. One month after the administration of FOLactis treatment, a subsequent CT examination revealed the complete resolution of malignant pleural effusion (MPE).

Introduction

Malignant pleural effusion (MPE) commonly occurs as a consequential complication in patients with advanced cancer, resulting from the metastatic spread of tumor cells to the pleural space [1]. MPE can give rise to respiratory distress, thoracic constriction, and dyspnea, significantly impairing patients’ quality of life and curbing overall survival [2]. Approximately 25% of individuals diagnosed with lung cancer already present with the accompanying complication of MPE at the time of their diagnosis [3]. Conventional therapeutic modalities for managing MPE encompass a range of approaches, such as thoracentesis, thoracic drainage, pleurodesis, placement of indwelling pleural catheters, and administration of thoracic perfusion medications, among others [4]. However, these methods merely provide symptomatic relief to the patients. In this report, we present a compelling case demonstrating the remarkable resolution of MPE in an advanced lung cancer patient through the utilization of intrathoracic instillation of FOLactis, an innovative in situ vaccine comprising lactic acid bacterium.

Case report

In February 2022, the patient sought medical attention at a local hospital, presenting with an inexplicable, persistent cough accompanied by chest tightness and exertional dyspnea. Thoracic CT showed an occupying lesion in the middle lobe of the right lung and a right pleural effusion. And the multiple intrahepatic occupying lesions, the bony destruction of the vertebral body. Subsequent bone scintigraphy demonstrated the presence of widespread bone metastases, indicating the systemic dissemination of cancer cells. Moreover, the results obtained from the liver puncture biopsy displayed features consistent with moderately to poorly differentiated adenocarcinoma. Immunohistochemistry (IHC) indicate Ki67 (60%+), Villian (−), TTP-1 (+), CDX-2 (−), NapsinA (+), CK20 (−), GPC-3 (−), SATB-2 (−), Arg-1. The cranial and thoracic spine MR findings revealed the presence of bilateral cerebral and cerebellar metastases, with evidence of intracranial hemorrhage observed in the left-sided metastatic lesion. The patient received a diagnosis of stage IV adenocarcinoma of the lung, characterized by widespread metastatic involvement in various sites, including the right pleura, liver, bone, brain, and bilateral adrenal glands. Furthermore, the patient’s gene sequencing analysis revealed the presence of Her2 amplification, thereby indicating a potential therapeutic target. Consequently, the patient underwent a comprehensive treatment regimen consisting of bevacizumab, Herceptin, Pemetrexed, and Carboplatin, which was administered for a total of six cycles at an external medical facility, commencing on 21/02/2022 (Fig. 1).

Fig. 1.

The course of the patient’s treatment

On July 4, 2022, the patient presented at our medical facility for a follow-up examination, and the imaging results indicated stable status of all lesions, signifying no significant changes in their size or characteristics. However, the patient’s right pleural effusion exhibited limited response to treatment, failing to demonstrate significant reduction, while intermittent chest tightness and discomfort persisted. Examination of the pleural effusion cytology unveiled the presence of heterogeneous cells (Fig. 2A). Chest fluid routine examination results: Sample volume 6 ml, color tea-yellow, appearance relatively clear, nucleated cell count 339.0 × 10⁶/L, body fluid white blood cell count 323.0 × 10⁶/L, lymphocyte ratio 87.0%, neutrophil ratio 13.0%, lymphocyte count 281.0 × 10⁶/L, neutrophil count 42.0 × 10⁶/L, protein qualitative test positive (+). Pleural fluid biochemical analysis: lactate dehydrogenase 228 U/L, total protein 47.3 g/L, albumin 34.0 g/L, globulin 13.3 g/L, albumin/globulin ratio 2.56, adenosine deaminase 8.7 U/L. Pleural effusion tumor marker results: Carcinoembryonic antigen (CEA) 18.84 ng/ml, Carbohydrate antigen 125 (CA125) 314.30 U/ml, Carbohydrate antigen 19-9 (CA19-9) 8.00 U/ml, Carbohydrate antigen 72-4 (CA72-4) 66.40 U/ml, Carbohydrate antigen 242 (CA242) 2.79 U/ml.

Fig. 2.

A Cytological examination of pleural effusion. B CT image showed the changes in the patient’s pleural effusion

On July 29, 2022, the patient was readmitted for further treatment, and a subsequent CT reevaluation revealed that the volume of the right pleural effusion remained unchanged, comparable to the previous examination. The patient presents with cachexia secondary to advanced malignancy, resulting in severe immunodeficiency and an inability to withstand the physiological stress of pleurodesis and the subsequent postoperative recovery, thereby conferring a prohibitively high perioperative risk. Furthermore, routine analysis of the pleural effusion demonstrates a pronounced neutrophilic leukocytosis, indicative of a significant inflammatory or infectious process within the pleural cavity. In this context, performing pleurodesis carries a substantial risk of disseminating infection, which could precipitate a clinical deterioration. Consequently, the patient opted to enroll in the Center’s clinical trial titled “R-ISV-FOLactis.” Building upon the foundation of maintenance therapy comprising bevacizumab, Herceptin, and Pemetrexed, the patient underwent a comprehensive treatment regimen involving the administration of the innovative Lactobacillus FOLactis in situ vaccine, alongside radiotherapy. The radiotherapy target is the liver metastasis site. The prescribed dose of radiotherapy is PGTV: 5 Gy*3f, PTV: 3 Gy*3 f. On August 25, 2022, a follow-up CT scan revealed overall stability in the patient’s condition, accompanied by a notable decrease in the size of the right pleural effusion (Fig. 2B). Patients had decreased levels of tumor markers such as CEA, CA724, CA125 and CYPF21-1 (Fig. 3A). After receiving intrathoracic injection of FOLactis, the patient’s immune system was activated, leading to an increase in the levels of PD-1⁺CD8⁺ lymphocytes, as well as CD103⁺CD8⁺ and CD11C⁺CD86⁺HLA-DR⁺ lymphocytes (Fig. 3B).

Fig. 3.

A The levels of tumor markers in patient. B The levels of peripheral blood lymphocytes in patient

Discussions

MPE is a frequently encountered complication in advanced lung cancer cases. In patients with advanced cancer, MPE is a frequent complication and a principal contributor to a severely diminished quality of life. The effusion induces debilitating symptoms, including persistent dyspnea, chest discomfort, and profound fatigue. Unfortunately, the prognosis for lung cancer patients with MPE remains discouraging, with an average overall survival of merely 8.5 months [5]. Intracavitary infusion of various agents is a commonly employed treatment approach for MPE. Traditional therapies encompass biological immune agents, chemotherapeutic drugs, and sclerotherapy agents; however, their effectiveness in treating MPE is limited. Notably, studies have indicated that tumor cells immersed in the pleural space tend to produce substantial amounts of vascular endothelial growth factor (VEGF) [6]. In an attempt to address MPE in patients with non-small cell lung cancer (NSCLC), intrathoracic infusion of bevacizumab in combination with pemetrexed or cisplatin has demonstrated improved response rates and enhanced quality of life [7]. Regrettably, despite undergoing treatment with intrathoracic infusion of bevacizumab combined with chemotherapy, the patient did not experience a reduction in pleural effusion or relief from chest tightness. These observations suggest that this particular treatment regimen proved ineffective for the patient in question.

Extensive research into the pathophysiology of malignant pleural effusion (MPE) has shed light on its composition, which includes immunogenic exosomes, immune cells, and immune factors [8]. However, as the tumor progresses, MPE becomes functionally “cold,” lacking an effective immune response. Therefore, a crucial treatment approach involves converting MPE from a “cold” to a “hot” state. Intrathoracic infusion of immune adjuvants has been the subject of long-standing investigation. Previous studies have demonstrated that intrathoracic infusion of interleukin-2 (IL-2) reduces the expression of PD-1 in MPE, increases the expression of granulysin B and interferon γ, and enhances the proliferation of CD8⁺ T cells [9]. Another promising immunobiologic agent is OK-432, a lyophilized mixture of group A Streptococcus pyogenes and penicillin G. In a phase II clinical trial involving patients with non-small cell lung cancer and MPE, intrathoracic injections of bleomycin, OK-432, or cisplatin/etoposide were administered, with OK-432 demonstrating the highest disease control rate of 75.8% [10]. Furthermore, in a study involving non-small cell lung cancer patients with MPE, intrathoracic infusion of PD-1 antibodies led to a significant reduction in malignant pleural effusion volume [11]. In summary, intrathoracic injection of immunobiologics represents a promising strategy to improve the immunosuppressive environment associated with MPE. This approach aims to transform MPE into a more immunologically active state, providing new avenues for treatment.

FOLactis represents a groundbreaking approach as a probiotic food-grade in situ vaccination, utilizing Lactococcus lactis as its base and expressing a fusion protein comprising Fms-like tyrosine kinase 3 ligand and co-stimulator OX40 ligand [12]. Previous studies have demonstrated that intrathoracic infusion of FOLactis elicits the activation of natural killer cells and cytotoxic T lymphocytes, leading to a robust immune response specific to tumor antigens and yielding superior systemic antitumor efficacy. Notably, patients undergoing intrathoracic infusion of FOLactis exhibited a remarkable reduction in malignant pleural effusions, accompanied by a decrease in associated tumor markers. Moreover, the examination of lymphocyte levels in the patient’s peripheral blood following treatment revealed elevated levels of PD-1⁺CD8⁺, CD103⁺CD8⁺, and CD11C⁺CD86⁺HLA-DR⁺ lymphocytes in the peripheral blood, as depicted in Fig. 3B. The noteworthy aspect is that until the administration of FOLactis, the malignant pleural effusion had persisted without any reduction. This highlights the limited effectiveness of conventional treatments for this particular patient. In contrast, the CT scan results and blood test outcomes subsequent to intrathoracic infusion of FOLactis provide compelling evidence that the patient is indeed benefiting from this innovative therapeutic approach.

The management of malignant pleural effusion has proven to be challenging, with limited effective treatment options available. However, this particular case sheds light on several significant findings. Firstly, FOLactis demonstrates the anti-tumor capabilities and successfully activates T-cells following its administration. This highlights the potential of FOLactis as a therapeutic intervention. Secondly, intrathoracic infusion of FOLactis proves to be the effective approach in controlling malignant pleural effusions. This emphasizes the clinical benefits of utilizing FOLactis in managing this complex condition. Lastly, the use of intrathoracic immunotherapy shows promise in reversing the immunosuppressive environment associated with malignant pleural effusion. This suggests a potential paradigm shift in the treatment of MPE, as immunotherapy holds the potential to enhance the immune response and improve patient outcomes. However, these current findings are based on individual cases. More clinical trials are needed to verify them. Overall, these findings underscore the significance of FOLactis and intrathoracic immunotherapy in addressing the challenges posed by malignant pleural effusion and offer hope for more effective treatment strategies in the future.

Author contributions

Jie Shen and Baorui Liu conceived and designed the experiments. Mingzhen Zhou, Juan Zhang, Sihui Zhu and Yan Zhao collected and analyzed data. Mingzhen Zhou wrote the manuscript. Jie Shen and Baorui Liu reviewed and edited the manuscript. All authors interpreted the data, critically revised the manuscript for important intellectual contents and approved the final version.

Funding

The study was supported by the Project of Chinese Hospital Reform and Development Institute, Nanjing University (NDYGN2023002); The Hospital Management Research of Jiangsu Province (No. JSYGY-3-2023-618); and Medical Science and Technology Development Foundation of Nanjing (No. YKK22095).

Data availability

All data generated or analyzed during this study are included in this published article.

Declarations

Ethics approval and consent to participate

This study protocol was reviewed and approved by ethics committee of Comprehensive Cancer Center of Drum Tower Hospital of Nanjing University and Drum Tower Hospital of Nanjing University. The patients/participants provided their written informed consent to participate in this study and agree to publish the relevant content. Registry and the Registration No. of the study/trial: N/A. Animal Studies: N/A.

Consent for publication

Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request.

Competing interests

The authors declare no competing interests.