Intrapleural Staphylococcal Superantigen Induces Resolution of Malignant Pleural Effusions and a Survival Benefit in Non-Small Cell Lung Cancer

doi:10.1378/chest.126.5.1529

Chest

Volume 126, Issue 5, November 2004, Pages 1529-1539

https://doi.org/10.1378/chest.126.5.1529 Get rights and content

Background:

Malignant pleural effusion (MPE) may occur in up to 50% of patients with non-small cell lung cancer (NSCLC). The majority of these patients have a poor performance status and a dismal prognosis, with survival duration ranging from 2 to 3 months. Since these patients are typically symptomatic from their MPE, prompt treatment is required. Patients with symptomatic MPE from NSCLC and poor performance scores (Eastern Cooperative Oncology Group [ECOG] score ≥ 2, Karnofsky performance status [KPS] score < 50) are generally not offered systemic chemotherapy. Treatment is palliative and includes intrapleural catheter drainage or chemical pleurodesis with talc, doxycycline, or bleomycin. None of the latter modalities prolong survival.

Objective:

Our goal was to investigate the toxicity and therapeutic effect of a new therapeutic agent, Staphylococcus aureus superantigen (SSAg), a powerful T-cell stimulant administered intrapleurally to unselected, consecutive patients with MPE from NSCLC (stage IIIb with pleural effusion) and a poor performance status. By providing direct access of the SSAg to the bronchial and mediastinal lymphatics, we predicted that intrapleural administration of SSAg would induce resolution of MPE and prolong survival in this population with advanced NSCLC and a limited prognosis.

Methods:

Fourteen consecutive, unselected patients with MPE from NSCLC and a median pretreatment KPS score of 40 (range, 10 to 60) received pleural instillation of SSAg, 100 to 400 pg, once or twice weekly (mean, 3.7 ≤ 1.3 treatments [≤ SD]) until the pleural effusions resolved. They were evaluated for drug toxicity, resolution, duration of MPE, and survival.

Results:

Other than mild fever (maximum grade 2), toxicity of SSAg treatment was trivial and notably devoid of respiratory distress or hypotension. Eleven patients had a complete response (CR), and 3 patients had a partial response of their MPE. In 12 patients, the response endured for > 90 days, with a median time to recurrence of 5 months (range, 3 to 23 months). The median survival for the SSAg-treated group was 7.9 months (range, 2 to 36 months; 95% confidence interval [CI], 5.9 to 11.4 months), compared to a median survival of 2.5 months (range, 0.1 to 57 months; 95% CI, 1.3 to 3.4 months) for 18 consecutive, unselected patients with MPE from NSCLC (stage IIIb) treated with talc poudrage (p = 0.044). Survival duration of all 14 SSAg-treated cases and 13 talc-poudrage-treated patients with comparable pretreatment KPS (range, 10 to 60; median, 40 and 30, respectively), and distribution (p = 0.5) was 7.9 months (95% CI, 5.9 to 11.4 months) and 2.0 months (95% CI, 0.4 to 2.9 months), respectively (p = 0.0023). Nine of 14 patients treated with SSAg survived > 6 months, 4 patients survived > 9 months, and 3 patients survived > 350 days. One of the patients in the CR group has survived 36 months. None of the 13 talc-treated patients survived > 6 months.

Interpretation:

In 14 unselected, consecutive patients with MPE from NSCLC and poor pretreatment performance (median KPS of 40), the intrapleural administration of SSAg was efficacious in resolving the MPE without any clinically important adverse effects. SSAg-treated patients with a median KPS of 40 (range, 10 to 60) had a median survival that exceeded that with talc poudrage, and was comparable to current systemic chemotherapy used in patients with KPS ≥ 70 status. SSAg treatment is simple to perform, minimally invasive, and does not require hospital time. It may be an attractive alternative to existing palliative modalities for stage IIIb patients with MPE and poor performance who are not candidates for systemic chemotherapy.

Section snippets

SSAg-Treated Patients

From February 1999 to October 2002, 14 consecutive and unselected patients with NSCLC and MPE were treated with SSAg. Patients were required to have NSCLC with, at least, 350 mL of pleural fluid. Systemic chemotherapy and all other biological response-modifying agents with antitumor activities were discontinued at least 1 month prior to initiating treatment. Radiotherapy was allowed provided it was not focused on the site of the pleural effusion. Pleural effusions were confirmed by chest

Patient Characteristics

Fourteen unselected, consecutive patients with MPE from NSCLC were treated with SSAg; all were men with a median age of 67.5 years (range, 46 to 82 years). Eight patients had COPD or coronary artery disease. Of the NSCLCs, 10 were adenocarcinomas and 4 were squamous cell carcinomas. Six of 14 patients received prior radiation or chemotherapy. In the remaining eight patients, MPE was the first sign of malignancy. In 11 patients, the MPE was associated with a radiographically evident tumor mass.

Discussion

We found that intrapleural administration of SSAg to 14 unselected, consecutive patients with MPE from NSCLC resulted in resolution of the MPE within 1 month after concluding treatment with persistence for > 90 days in 12 of 14 patients. In several cases, resolution lasted for as long as 6 months, 8 months, 12 months, and 15 months, with a median time to recurrence of 5 months. The response rate (100%) for resolution of the MPE exceeded that for talc, bleomycin, doxycycline, and indwelling

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Intrapleural immunotherapies have emerged as a prominent field in treating malignant pleural effusion (MPE). Among these, bacteria-based intrapleural therapy has exerted an anti-MPE effect by immuno-stimulating or cytotoxic properties. We previously engineered a probiotic Lactococcus lactis (FOLactis) expressing a fusion protein of Fms-like tyrosine kinase 3 and co-stimulator OX40 ligands. FOLactis activates tumor antigen-specific immune responses and displays systemic antitumor efficacy via intratumoral delivery. However, no available lesions exist in the pleural cavity of patients with MPE for intratumoral administration. Therefore, we further optimize FOLactis to treat MPE through intrapleural injection. Intrapleural administration of FOLactis (I-Pl FOLactis) not only distinctly suppresses MPE and pleural tumor nodules, but also significantly extends noticeable survival in MPE-bearing murine models. The proportion of CD103⁺ dendritic cells (DCs) in tumor-draining lymph nodes increases three-fold in FOLactis group, compared to the wild-type bacteria group. The enhanced DCs recruitment promotes the infiltration of effector memory T and CD8⁺ T cells, as well as the activation of NK cells and the polarization of macrophages to M1. Programmed death 1 blockade antibody combination further enhances the antitumor efficacy of I-Pl FOLactis. In summary, we first develop an innovative intrapleural strategy based on FOLactis, exhibiting remarkable efficacy and favorable biosafety profiles. These findings suggest prospective clinical translation of engineered probiotics for managing MPE through direct administration into the pleural cavity.
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Pleurodesis is used to obliterate the pleural space and is an effective therapeutic option for patients with recurrent effusions or pneumothoraces. A variety of surgical methods and chemical pleurodesing agents exist with different efficacy and side effect profiles. Talc is the most common and most effective agent available for chemical pleurodesis. Pleurodesis remains an important treatment modality for management of malignant effusions even with the advent of indwelling pleural catheters. There is growing interest to predict markers of successful pleurodesis and its role in patient survival.
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Citation Excerpt :
OK432 was not associated with any survival benefit in 5 randomised and 1 non-randomised studies, [38,41–44,46], although for one of those studies the comparator was intra-venous chemotherapy, suggesting that OK432 may be as effective as standard treatment [44]. Corynebacterium parvum was associated with longer survival in one non-randomised study [13], but no effect in 2 others (1 randomised7 and 1 non-randomised58), whilst Staphylococcus aureus superantigen was associated with longer survival in a single observational study [36]. This systematic review evaluating the effect of intra-pleural bacterial products on survival in malignant pleural effusions is the first to formally summarise the literature for this topic.
Intra-pleural bacteria are effective pleurodesis agents in malignant pleural effusions. However, their relationship with survival is unclear.
We undertook a comprehensive, structured evaluation of survival outcomes in adults with malignant pleural effusions treated with intra-pleural bacterial products.
Medline, Embase, Cochrane library, Clinical Trials Registers and Open Grey.
Randomised controlled trials and non-randomised comparative studies were included, if the population included adults with malignant pleural effusions. Interventions of interest were any intra-pleural bacterial product, compared with placebo, alternative intra-pleural drug, or no treatment. Survival outcomes were collected.
Study appraisal and synthesis methods: Two reviewers independently screened studies for eligibility, assessed papers for risk of bias and extracted data. Narrative synthesis was performed as high heterogeneity between studies precluded meta-analysis.
631 studies were identified, of which 14 were included. All were at high or unclear risk of bias in at least one domain. Six studies reported a survival benefit associated with intra-pleural bacterial products, whilst 8 reported no difference. Non-randomised studies and studies published prior to 2000 were more likely to report survival benefits.
There was high heterogeneity between studies, which limited the generalisability of findings. Publication bias may have affected the review as five full-text papers were unobtainable, and survival outcomes were missing in a further five.
There is a lack of high quality evidence regarding the relationship between intra-pleural bacterial products and survival.
Implications of key findings: Well-designed, prospective randomised trials are needed, to determine whether intra-pleural bacterial products can improve survival in pleural malignancy.
CRD42017058067.
Survival in patients with malignant pleural effusions who developed pleural infection: A retrospective case review from six UK centers
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Survival in patients with pleural infection was compared with 788 patients with MPE (known as the LENT [pleural fluid lactate dehydrogenase, Eastern Cooperative Oncology Group performance status, serum neutrophil to lymphocyte ratio, and tumor type] cohort) and with national statistics.
Of 672 IPCs inserted, 25 (3.7%) became infected. Most patients (20 of 25) had mesothelioma or lung cancer. Median survival in the pleural infection cohort appeared longer than in the LENT cohort, although this result did not achieve significance (386 days vs 132 days; hazard ratio, 0.67; P = .07). Median survival with mesothelioma and pleural infection was twice as long as national estimates for mesothelioma survival (753 days vs < 365 days) and double the median survival of patients with mesothelioma in the LENT cohort (339 days; 95% CI, nonoverlapping). Survival with lung and breast cancer did not differ significantly between the groups. Sixty-one percent of patients experienced early infection. There was no survival difference between patients with early and late infection (P = .6).
This small series of patients with IPCs for MPE suggests pleural infection may be associated with longer survival, particularly in patients with mesothelioma. Results did not achieve significance, and a larger study is needed to explore this relationship further and investigate whether the local immune response, triggered by infection, is able to modulate mesothelioma progression.
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View all citing articles on Scopus

: Supported in part by PHS Grant P20-RR15587 (to Dr. Bohach).

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Chest

Clinical InvestigationsTHE PLEURAIntrapleural Staphylococcal Superantigen Induces Resolution of Malignant Pleural Effusions and a Survival Benefit in Non-Small Cell Lung Cancer

Background:

Objective:

Methods:

Results:

Interpretation:

Section snippets

SSAg-Treated Patients

Patient Characteristics

Discussion

Am J Med

Clin Chest Med

Ann Thorac Surg

Chest

Chest

Chest

Crit Rev Oncol Hematol

Lung Cancer

Am J Med

Eur J Cancer Clin Oncol

Chest

Cytokine

Pleural fluid pH in malignant effusions

Ann Intern Med

Chemical pleurodesis for malignant pleural effusions

Ann Intern Med

Management or malignant pleural effusions

Eur Respir J

Pleural diseases.

Malignant pleural and pericardial effusions

Effusions in clinical oncology

A randomized comparison of indwelling pleural catheter and doxycycline pleurodesis in the management of malignant pleural effusions

Cancer

Lung cancer with malignant pleural effusion: clinical and survival characteristics [abstract]

Am J Respir Crit Care Med

The Staphylococcal enterotoxins and their relatives

Science

Tumoricidal response induced by cytosine arabinoside after plasma perfusion over protein A

Science

Staphylococcal and streptococcal exotoxin (superantigen) induced regression of established tumor in vivo. Proceedings of International Workshop on Superantigens.

Clinical Investigations
THE PLEURA
Intrapleural Staphylococcal Superantigen Induces Resolution of Malignant Pleural Effusions and a Survival Benefit in Non-Small Cell Lung Cancer