Growth arrest of a refractory vestibular schwannoma after anti-PD-1 antibody treatment

Abstract

A 25-year-old man presented with left-sided hearing loss, blurred vision and papilloedema. Imaging revealed a large, left-sided, contrast-enhancing cerebellopontine mass causing obstructive hydrocephalus, consistent with vestibular schwannoma (VS). Following an incomplete resection via retrosigmoid craniotomy at an outside facility, he was referred to our department, and cerebrospinal fluid diversion followed by repeat resection was recommended. A subtotal resection was achieved, and the patient was subsequently treated with adjuvant stereotactic radiosurgery (SRS). Progressive interval growth was observed on serial post-SRS MRI studies; correspondingly, at 31 months after treatment, the patient was initiated on antiprogrammed-death receptor 1 (PD-1) antibody treatment with pembrolizumab. Growth arrest was noted on subsequent serial imaging studies, which have been maintained for a total of 30 months since initiation of a 18-month anti-PD-1 course of therapy. Additional case accumulation and translational study is required to better characterise this therapeutic strategy; however, PD-1/programmed death-ligand 1 inhibition may offer a promising salvage therapy for refractory VS.

Background

Vestibular schwannomas (VSs) are benign tumours arising from the myelinating Schwann cells supporting the vestibulocochlear nerve. Small, asymptomatic or stable tumours may be safely observed, while treatment strategies for large or growing tumours include microsurgical resection and stereotactic radiosurgery (SRS), with medical treatments largely excluded from the conventional armamentarium. The VS immune microenvironment is an area of evolving relevance for translational therapeutics. Programmed death-ligand 1 (PD-L1) is pathologically active across a range of malignant and benign diseases, in which it most frequently binds to programmed-death receptor 1 (PD-1) on immune cells, inhibiting antitumour immunity.^{1 2} At present, monoclonal antibodies targeted against both PD-1 and PD-L1 are approved by the US Food and Drug Administration (FDA) for use in melanoma, non-small-cell lung cancer, head and neck squamous cell carcinoma, renal cell carcinoma, Hodgkin’s lymphoma, urothelial carcinoma and merkel-cell carcinoma, with numerous phase 2 and 3 trials ongoing for other indications.^{3 4} Preliminary laboratory data in VS have demonstrated a significant association between pathological PD-L1 overexpression and phenotypically aggressive tumour behaviours, including rapid growth, post-treatment recurrence/progression and poor facial nerve outcomes.⁵ We report the index case of growth arrest in a vs that failed multiple resections and SRS, which subsequently responded to anti-PD-1 immunotherapy.

Case presentation

A 25-year-old man presented with new left-sided hearing loss and blurred vision with papilloedema. Initial imaging demonstrated a large, left, contrast-enhancing, cerebellopontine angle and internal auditory canal lesion associated with marked brainstem compression causing obstructive hydrocephalus, highly consistent with VS (figure 1A). He underwent surgical resection at an outside institution via retrosigmoid craniotomy, which resulted in modest debulking only (figure 1B). He was referred to our facility approximately 6 months after surgery, and on initial assessment was noted to have progressive clinical hydrocephalus with worsening headaches, gait imbalance and visual blurring secondary to papilloedema, as well as interval tumour growth (figure 1C). Our team recommended urgent placement of a ventriculoperitoneal shunt, followed by repeat tumour resection via translabyrinthine approach. Both operations proceeded uneventfully, an aggressive subtotal resection was achieved during the resection, which was halted due to unfavourable planes and a splayed and densely scarred facial nerve, which could not be safely dissected off the residual tumour. The patient recovered well, with near-normal House-Brackmanngrade II facial nerve function and eventual resolution of hydrocephalus. His postoperative course was complicated by a cystic cerebellar abscess, for which he required an open incision and drainage as well as intravenous antibiotics. He again recovered uneventfully, and at approximately 6 months after surgery the tumour residuum was treated with SRS to a margin dose of 13 Gy at the 50% isodose line and a treatment volume of 9.2 cm³ (figure 1D). Routine post-SRS surveillance MRIs demonstrated a 13.0 cm³ residual tumour volume at approximately 6 months after surgery, which was unchanged on follow-up studies at 12 and 18 months. At 31 months postsurgery, updated MRI demonstrated marked subclinical disease progression with volumetric expansion to 36.3 cm³ (figure 1E).

Figure 1.

(A) Head CT imaging at time-of-diagnosis demonstrated a large, hyperdense, contrast-enhancing, extra-axial mass lesion compressing the adjacent brainstem effacing the fourth ventricle, consistent with vestibular schwannoma. (B) T1-weighted contrast-enhanced MRI of the brain following surgery at an outside institution confirmed central debulking with a moderately large tumour residuum associated with persistent brain stem mass effect. (C) Interval imaging at the time of our initial consultation approximately 6 months later confirmed marked expansion of the residual tumour. (D) MRI following repeat resection by our team demonstrated aggressive subtotal resection, with a modest ventral residuum, and decompression of the brain stem; the tumour remnant underwent adjuvant treatment with stereotactic radiosurgery at 6 months after surgery. (E) Postradiosurgery imaging remained stable at 6, 12 and 18 months after treatment (not shown); however, subsequent surveillance MRI at 31 months identified new moderate tumour growth, ultimately prompting pembrolizumab therapy. (F) Interval MRI at 30 months following initiation of pembrolizumab demonstrates stable disease without evidence of interval progression.

Treatment

Given the finding of slow but progressive tumour growth after multiple resections and SRS, as well as the patient’s young age, we recommended consideration for immune checkpoint inhibitor therapy. In consultation with our neuro-oncology team, the patient was initiated on the anti-PD-1 antibody, pembrolizumab. The dosing schedule was based on an adapted protocol for off-label use at 2 mg/kg, with a final infusion dose of 200 mg once every 3 weeks and routine laboratory monitoring for drug toxicity throughout the course of treatment.

Outcome and follow-up

Since initiation of therapy, the patient underwent serial MRI studies every 6–12 months, with no evidence of nodular growth noted during the total follow-up period of 30 months documented since initiation of pembrolizumab (figure 1F). Following infusions, the patient did report fatigue, but no other evidence of an adverse drug effect was observed, and no laboratory aberrancies were noted. Due to adverse impacts of fatigue on quality-of-life, treatment was discontinued at approximately 18 months after initiation, with no tumour progression or other adverse treatment effects noted on multiple MRI studies and clinic visits during the subsequent 12 months of follow-up.

Discussion

We report the index case of growth arrest in a postresection, post-SRS, treatment-refractory VS, most likely attributable to medical treatment with the anti-PD-1 antibody pembrolizumab. This novel treatment strategy was motivated by several key findings in the translational neurosurgery and neuro-oncology literature. Immune-checkpoint inhibitors targeting the PD-1/PD-L1 axis have demonstrated robust results across a host of human malignancies in clinical trial settings, with randomised evidence supporting the use of humanised antibodies in the treatment of melanoma, non-small-cell lung cancer and several other key diseases.^1–4 Recent observations have indicated that PD-1/PD-L1 inhibition acts synergistically with SRS in the treatment of brain metastases, suggesting that agents are both active against multiple tumour types, and able to penetrate the CNS at routine doses without marked toxicity.^6–8

No human trial of immunotherapy for benign intracranial schwannoma has been reported to date; however, translational studies from both murine in vivo models and in vitro studies of human VS tissue have provided compelling evidence that dysregulation of PD-1/PD-L1 signalling is a powerful driver of phenotypically aggressive behaviour, including post-treatment recurrence/progression. In the present case, several key factors informed clinical decision making with respect to consideration of this novel therapy. The patient was a young man, and therefore at higher risk of recurrence, both due to his considerable actuarial survival, and the previously reported increased incidence of aggressive behaviour when large VSs are identified in young patients.^{9 10} Further, at the time of pembrolizumab initiation, he had undergone a preliminary resection by an outside facility, and failed both aggressive repeat resection at our institution and SRS, suggesting that he may have been at particularly increased risk of additional tumour progression.^{11 12} However, the noted tumour growth was slow and his hydrocephalus was resolved, indicating that consideration for a novel intervention would be unlikely to result in an unfavourable risk/benefit calculus. This is particularly emphasised in the context of his multiple prior resections, as both microsurgical resection and SRS are known to increase the difficulty of future interventions, and therefore, the potential for an unfavourable facial nerve outcome after either a third resection or a second course of SRS.^13–15

As we have previously described, phenotypically aggressive VSs appear to demonstrate immune-evasive behaviours, marked by negative immune regulators and increased density of tumour-associated macrophages (TAMs).^{5 16–19} These findings have in turn been associated with preoperative and postoperative VS growth, as well as unfavourable facial nerve outcomes and increased risk of treatment complications.^{5 16–19} The secretion of high levels of PD-1 by certain tumours is associated with the deactivation of anti-tumour cytotoxic T-cells and TAMs, which leads to decreased phagocytosis, reduced immune cell recruitment and increased tumour growth.^20–22 Therefore, the efficacy of anti-PD-1 antibodies is most likely a consequence of interrupting this pathological signalling, which would have otherwise downregulated antitumour immune system activity. Downregulating the anti-immune system tumourous response likely enables increased TAMs and T-cells recruitment and anti-tumour activity, targeting the tumour cells and arresting tumour growth.^{1–5 23}

Our anecdotal experience with this novel treatment was associated with favourable tumour response and overall clinical outcome. Our patient did experience marked, chronic fatigue after each treatment—the most common drug toxicity associated with this agent, and one which was ultimately sufficient to prompt discontinuation of therapy; after which his symptoms subsided. He did not encounter any of the other commonplace pembrolizumab side effects, which are fortunately mild in most patients, and typically include pruritus or rash in 18%–26%.²³ Given the patient’s age, another important consideration is the potential for acquired, chronic resistance to immunotherapy. In the setting of less aggressive disease, or where other treatment options were available, further delay might be warranted prior to initiation of immunotherapy, particularly given the patient’s age. Similarly, should clinical recurrence be observed, the choice of anti-PD-1/anti-PD-L1 agent for rechallenge may present a decision-making challenge. Most likely, we would first attempt another course of pembrolizumab, with consideration for an alternative anti-PD-1/anti-PD-L1 agent if an early response was not noted. We suggest that further study in a focused Phase I/II setting for refractory VS would likely have an acceptable safety profile, comparable to preceding trials of the same agents, but with healthier patients due to the non-malignant diagnoses and differences in median age.

With regard to disease control, the present case suggests the possibility of an association between pembrolizumab therapy and growth arrest; however, numerous potential confounders may also account for the observed changes. The true incidence of VS tumour growth stabilisation without treatment following initial disease progression is poorly understood, as serial imaging studies confirming VS growth almost universally prompt treatment. Correspondingly, one can also imagine that the observed growth arrest is due to an unusual natural history, which has a spurious correlation with the pembrolizumab treatment. This possibility is further emphasised by the low PD-L1 staining noted on immunohistochemistry (figure 2), although interpretation of that data is complicated by the lack of PD-1 staining, delayed specimen processing, and limitation to the single PD-L1 clone that is most closely associated with pembrolizumab sensitivity. Similarly, initial swelling or even interval growth of VS after SRS has been reported, with a delay of months or even years prior to the observation of true growth arrest or tumour regression.^24–27 Indeed, our patient may have experienced an idiosyncratic reaction to SRS, in which an aggressive tumour continued to grow for longer before the benefits of irradiation were observed. Although this is impossible to exclude using the available data, we do note that most tumours following this pattern of behaviour undergo a more characteristic set of changes in their MRI signal characteristics, such as pronounced loss of central enhancement.²⁴ Finally, there is a remote possibility that the patient was exposed to an unrelated treatment that may have impacted the growth arrest we observed, such as chronic aspirin use, which has been inconsistently shown to modulate VS growth in certain observational studies. Given that the patient is a reliable historian overall, and that the great majority of his medical care is centred at our facility, this would be an exceptional omission, and so we conclude that it is not likely to explain the observed findings.

Figure 2.

Immunohistochemistry for PD-L1 clone 22C3 demonstrated scattered areas of positive staining, with a standardised combined score of 1%. PD-L1, programmed death-ligand 1.

Patient’s perspective.

Pembrolizumab as a possible treatment for my vestibular schwannoma was discussed a few years after we saw that the other treatments were not working. My neurosurgeon brought it up in a way that made it sound like it was a promising option, although experimental, and so not a treatment that was approved or that would be covered by insurance. At that point, I was willing to try anything to stay away from another surgery.

While actively receiving pembrolizumab treatments I felt OK. It was not until a few hours later that I felt a little tired, but all in all, I felt OK. I was not able to go to the gym that day or the next and I usually took off work the following day just to rest up. The fatigue was worse some days than others, so I made sure I ate and stayed hydrated. My life was only adjusted for a day or two after each infusion. I didn’t go to the gym because I was tired and didn’t want to push myself. I also did not work the day after infusion, just to make sure nothing weird would happen—which it never did, but to be safe I stayed home. As compared with the other treatments, pembrolizumab was definitely not even the same ball game. Surgery and radiation took a LOT out of me, even just walking or showering by my self was difficult. After pembrolizumab treatments, although I was tired, overall I was able to continue a somewhat normal life and be independent.

My overall outlook at first was sceptical. Pembrolizumab was something I wasn’t sure of, but I had to try something, because everything else failed at stopping the tumour from growing. I was a little nervous, because when I thought about chemotherapy, it seemed like the worst possible treatment, but in reality it was the complete opposite. I had my days where I was exhausted, but I was always able to carry on. I was not as strong as I was before treatments, because I didn’t work out as much after the treatment days, but as soon as we stopped treatments, I gained all my energy back over a month or so. Today, I’m at the gym 4–5 days a week lifting weights, swimming, or doing cardio like I never even had the treatment. In the long haul, I am glad I made the decision to go with the treatments, as I’m now at a point where I don’t worry about the tumour too much until I have my MRI every 6 months or so, and I’m able to do the things I want to do without constant worry.

Learning points.

• The current study represents the first report of antiprogrammed-death receptor 1 antibodies therapy applied to vestibular schwannoma (VS), in this case a refractory, postresection, poststereotactic radiosurgery tumour.

• Given the observed growth arrest, immune-checkpoint inhibitor therapy may have a role in refractory VS, and warrants further evaluation via additional case accumulation and, if positive, consideration for randomised assessment.

• The initial clinical results of the current study are congruent with preceding basic science data regarding the immune microenvironment for VS and the role of abnormal programmed death-ligand 1 signalling in phenotypically aggressive disease.

• Novel medical therapies for refractory VS is an important area of translational need.