Original article
Quadruple immunotherapy of Bacillus Calmette-Guérin, interferon, interleukin-2, and granulocyte-macrophage colony-stimulating factor as salvage therapy for non–muscle-invasive bladder cancer

https://doi.org/10.1016/j.urolonc.2017.07.024Get rights and content

Highlights

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  • Incomplete immunostimulation has been proposed as a cause of BCG failure.

  • A total of 52 patients treated with quadruple immunotherapy were retrospectively reviewed.

  • A total of 53% of patients were disease-free 2 years after induction and maintenance therapy.

  • Quadruple immunotherapy was effective and warrants further comparative evaluation.

Abstract

Background

Bacillus Calmette-Guérin (BCG) is the most effective initial intravesical therapy for high-grade non–muscle invasive bladder cancer, but many patients still fail. Combination intravesical BCG and interferon (IFN) will salvage some patients but results remain suboptimal.

Objective

We hypothesized that further immunostimulation with intravesical interleukin-2 and subcutaneous granulocyte-macrophage colony-stimulating factor may improve response to intravesical BCG and IFN in patient with prior BCG failure(s).

Methods

A retrospective review was performed. Patients received 6 treatments of quadruple immunotherapy (intravesical solution with one-third dose BCG, 50 million units IFN, and 22 million units interleukin-2, along with a 250-mcg subcutaneous sargramostim injection). Surveillance began 4 to 6 weeks after treatment completion. Patients received maintenance if recurrence-free. Success was defined as no recurrence (bladder or extravesical) and bladder preservation. Analysis was performed by Kaplan-Meier method (P<0.05).

Results

Fifty-two patients received treatment with a median recurrence follow-up of 16.3 months and overall follow-up of 41.8 months. All patients had at least 1 prior BCG failure and 13% had 2 or more prior failures. Only 3 patients (6%) were unable to tolerate full induction. Treatment success was 55% at 1 year, and 53% at 2 years. Thirteen patients (25%) underwent cystectomy at a median time of 17.3 months with disease progression to T2 in 1 patient and T3 in 2 patients. No patients had positive surgical margins or positive lymph nodes.

Conclusions

In patients with non–muscle-invasive bladder cancer with prior BCG failure, quadruple immunotherapy demonstrated good treatment success in some patients and warrants further evaluation.

Introduction

Intravesical bacillus Calmette-Guérin (BCG) has demonstrated effectiveness in the treatment of high-grade (HG) non–muscle-invasive bladder cancer (NMIBC) after complete transurethral resection [1], [2] and is the standard of care for initial intravesical therapy [3]. However, BCG therapy will fail in 37% to 45% of patients treated over a 2-year span [4].

Although the immunologic mechanism for BCG failure has not been fully elucidated, it is known that BCG generates a vigorous host immune response [5], primarily a T-helper type 1 (Th1) response, with transient, large volume secretion of multiple cytokines. Interferon-gamma (IFN-γ) has specifically been shown to reflect the Th1 response [6]. IFN-a, interleukin-2 (IL-2), and granulocyte-monocyte colony-stimulating factor (GM-CSF), among others, have been shown to stimulate IFN-γ production [7], [8]. Inadequate immunostimulation from therapy has been postulated as a mechanism for BCG failure; more specifically, immunosenescence [9] is a possible rationale for the diminished therapeutic response in older patients [10]. Thus, the addition of other immunostimulatory agents to BCG, in theory, could augment the immune response and improve its effectiveness.

There have been prior attempts to induce further immunostimulation by combining BCG with other intravesical agents including IFN [4], [11] and IL-2 [12], [13], but no definitive improvements in recurrence rates have been identified. It is possible that the immune response in some patients remains below the threshold required for a clinical response. Further investigation of intravesical salvage therapy continues to be an important and necessary endeavor.

GM-CSF regulates myeloid lineage cells and is a systemic immunostimulatory agent commonly used by oncologists in patients receiving myelosuppressive intravenous chemotherapy to prevent febrile neutropenia [14]. GM-CSF has been identified as a costimulatory cytokine with BCG in the proinflammatory, IFN-producing pathway, and a potent agent for stimulating antigen presentation by dendritic cells [15]. Thus, the addition of exogenous GM-CSF to patients receiving intravesical BCG-based therapy could augment the proinflammatory response. To our knowledge, immune augmentation with GM-CSF has not been explored in NMIBC. In an attempt to amplify BCG-induced immunostimulation, we performed a pilot evaluation of salvage NMIBC therapy with quadruple immunotherapy (QIT), a concurrent intravesical instillation of BCG, IFN, and IL-2, along with a subcutaneous injection of GM-CSF.

Section snippets

Materials and methods

After Institutional Review Board approval, we retrospectively reviewed all prior BCG failure patients subsequently treated with QIT for NMIBC at our institution between June 2009 and May 2014. Patients were counseled about the American Urological Association recommendation at the time for cystectomy vs. the option of further intravesical therapy [3]. Candidacy for cystectomy was documented in the clinic record by the treating physician. After shared decision-making, if patients chose to proceed

Study population

Fifty-two patients received QIT. Patient characteristics are shown in Table 1. The median age at treatment was 69.5 years (range: 50–88). Forty-five of 52 patients (87%) had previously been treated with a single BCG-based induction course (BCG monotherapy or BCG/IFN), whereas 7 (13%) had received multiple induction BCG courses. The median number of prior induction BCG courses was 1 (range: 1–4). The BCG failure interval, defined as the time from the most recent prior BCG course to most recent

Discussion

We performed a pilot study on the use of QIT (intravesical therapy with BCG, IFN, and IL-2 augmented with subcutaneous GM-CSF) in the treatment of NMIBC. To our knowledge, this is the first report of using GM-CSF, in addition to intravesical salvage agents, to improve immunostimulation. Treatment, both induction and maintenance, was well tolerated with few side effects severe enough to affect the treatment schedule. In general, symptoms were consistent with those expected in patients treated

Conclusion

To our knowledge, this is the first study to report the tolerance and effectiveness of IL-2 and GM-CSF, in conjunction with BCG and IFN for the treatment of NMIBC. QIT resulted in prolonged treatment success in some patients and provides another salvage option.

Acknowledgments

Data were managed using REDCap software, supported by University of Iowa NIH, United States/CTSA program Grant 2UL1TR000442-06.

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Authors contributed equally.

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