Pembrolizumab plus Pharmacologic Ascorbate in the Treatment of Leiomyosarcoma

Leiomyosarcoma (LMS) makes up approximately 25% of soft tissue sarcomas, a rare heterogeneous group of neoplasms derived from mesenchymal stem cells. Although localized disease is potentially curable with surgery, metastatic LMS has a dismal prognosis, with no systemic treatment options that reliably offer durable response. Advanced or metastatic LMS is generally treated with anthracycline or gemcitabine-based chemotherapeutic regimens, which are associated with short progression-free survival (4–6 months), response rates around 20%, and significant morbidity related to cardiac, neurologic, hematologic, and constitutional side effects [1, 2].

The use of immune checkpoint inhibitors (ICI) has rapidly become a common treatment approach for several malignancies. By uninhibiting T-cell-mediated antitumor immunity through the programmed death 1 and cytotoxic T lymphocyte antigen 4 axes, ICIs can produce dramatic and durable treatment responses.

Despite these advances, the role of ICIs has yet to be elucidated in STS including LMS. While some sarcomas have shown susceptibility to immunotherapy, little data exist on the use of ICI in LMS, and existing data are low quality. ICIs alone have largely proven ineffective [3] thought to be due to their immunosuppressive tumor microenvironment.

Ascorbate, despite its controversial history as a pharmaceutical agent, has been considered in recent years as a legitimate anticancer therapy. Preclinical studies suggest immunotherapeutic benefits, largely related to improved T-cell and macrophage tumor infiltration [4]. Early clinical study of ascorbate for pancreatic cancer demonstrated its safety [5] and several clinical trials are ongoing, but the agent has yet to translate into treatment algorithms. We herein report 3 cases of pembrolizumab with concurrent ascorbate used to successfully treat metastatic LMS.

A 58-year-old woman with no significant past medical history presented to her gynecologist for evaluation of postmenopausal bleeding. She underwent hysteroscopic myomectomy, with pathology significant for uterine smooth muscle tumor of uncertain malignant potential. Six weeks later, a total abdominal hysterectomy with bilateral salpingo-oophorectomy was performed. Pathology resulted as LMS, 6 cm in greatest dimension, with negative programmed death ligand 1 and estrogen/progesterone receptor expression on immunohistochemistry. Approximately 1 year status post-total abdominal hysterectomy with bilateral salpingo-oophorectomy, the patient noticed mild abdominal distension and discomfort but was otherwise asymptomatic, and computed tomography (CT) scan of the chest/abdomen/pelvis revealed a new right lower lobe lung nodule as well as multiple enhancing lesions in the lower abdomen and pelvis, the largest of which measured 21 cm, concerning for metastatic LMS.

The patient underwent a course of radiation (30 Gray [Gy] in 10 fractions [fx]) to the largest abdominal lesion and with 200 mg pembrolizumab every 3 weeks (q3w) and concurrent weekly 25 g ascorbate. Monitoring imaging q3m showed persistent decreases in disease burden consistent with partial response. The patient continues to have a partial response 12 months after starting treatment (Fig. 1a).

A 53-year-old woman with no significant past medical history presented for evaluation of fatigue, presyncope, and erratic blood pressure. CT of the abdomen revealed a 7.1 cm complex heterogeneously enhancing hepatic mass with extensive involvement of the inferior vena cava as well as several peripheral satellite lesions in the superior left hepatic lobe and a 2.6 cm lesion of the right iliac bone, concerning for metastasis. Biopsy of the bony lesion showed atypical spindle cells and was found to be positive for muscle-specific actin and focally positive for desmin, consistent with metastatic LMS from a hepatic vein primary.

Treatment was initiated with radiation (30 Gy in 10 fx) with concurrent q3w 200 mg pembrolizumab and weekly 25 g ascorbate. Imaging was performed q3m which demonstrated a continuing partial response over the first 9 months of treatment. On CT imaging done at 12 months, new bone metastases were seen in the L3, L4, and S4 vertebrae, but the overall tumor burden had continued to decrease, so the decision was made to continue pembrolizumab and ascorbate but administer stereotactic body radiotherapy to the vertebral metastases. Twelve months after starting treatment, she continues treatment with continued decrease in overall tumor burden.

A 75-year-old woman with no significant past medical history presented to primary care with a fixed, firm mass on her right anterior lower leg which had been present for several months. Magnetic resonance imaging showed a 3.5 × 3.2 × 14.4 cm soft tissue mass surrounding the neurovascular bundle along the anterior lateral aspect of the tibia. There was no evidence of metastatic disease on CT imaging. Core needle biopsy showed at least intermediate grade undifferentiated pleomorphic sarcoma. Mass excision surgery was performed 1 month later followed by adjuvant radiation. The final diagnosis was Fédération Nationale des Centres de Lutte Contre le Cancer (FNCLCC) grade 2/3 pleomorphic LMS, with negative estrogen/progesterone receptor but positive (5%) programmed death ligand 1 expression on immunohistochemistry.

Ten months after diagnosis, CT imaging showed widely metastatic disease to the lungs and liver. She subsequently started single agent 200 mg pembrolizumab q3w. CT imaging after 3 months showed progression of the liver metastases, so 25 g ascorbate was added q3w with pembrolizumab. After 3 months, imaging showed stable disease. CT imaging done 3 months later showed partial response. The patient continues to have a partial response 17 months after the addition of pharmacologic ascorbate (Fig. 1b).

LMS may be uterine or nonuterine. While there is no consensus about the existence of differences in activity, treatment susceptibility, and prognosis between uterine and nonuterine LMS, both are known to be aggressive malignancies with high rates of metastasis and low survival. Although chemotherapy, including doxorubicin, can result in responses in a minority of patients, it rarely induces durable remission. These treatments also carry significant side effects including fatigue, alopecia, cytopenia, and cardiotoxicity.

Traditionally, sarcomas are thought to be immunologically cold, with limited responses to immunotherapy. Recent data cast doubt on this hypothesis. The recent phase II trial of cabozantinib with or without ipilimumab/nivolumab in STS including LMS demonstrated impressive long-term disease control with the addition of ICIs [6]. Further research is needed to identify treatments which can be combined with immunotherapy to increase checkpoint inhibitor efficacy.

Ascorbate is a water-soluble vitamin that contributes to many essential processes of the human body. Ascorbate is a known antioxidant secondary to its ability to easily donate electrons, having downstream effects on nicotinamide adenine dinucleotide phosphate oxidases and xanthine oxidase, reactive oxygen species producers. The anticancer properties of ascorbate are not completely understood, although it is postulated that its intracellular prooxidant abilities through hydrogen peroxide generation in tumors may contribute [4, 7]. Increasing evidence suggests that increased hydrogen peroxide can react with intracellular iron in iron-rich tumor cells while simultaneously acting as an antioxidant in normal tissue. Pharmacological ascorbate (intravenous infusions of vitamin C resulting in about 20 nm concentrations in plasma) has been trialed with varying efficacy, and no adverse effects, in combination with other treatment regimens including gemcitabine, doxorubicin, etoposide, cisplatin, and others [5, 7]. However, the optimal dosing strategy for pharmacologic ascorbate has yet to be elucidated. While 25 g q3w concurrently with pembrolizumab was effective and well tolerated in our series, a future phase 2 prospective study is indicated.

Pharmacological ascorbate has demonstrated several immune modulative effects involving multiple immune cell lines. Monocytes, macrophages, and neutrophils appear to have enhanced phagocytic activity when exposed to high concentrations of ascorbate. Natural killer cell function is also dramatically enhanced, with a high oral dose of vitamin C enhancing NK activity ten-fold in 78% of patients. With regards to the adaptive immune system, ascorbate is critical for T-cell development, maturation, and activity [8]. Furthermore, ascorbate inhibits multiple etiologies of T-cell death, including spontaneous apoptosis, growth factor withdrawal, and steroid induced T-cell death. Evaluation of pharmacological ascorbate in murine models has demonstrated synergism with anti-programmed death 1 checkpoint blockade by enhancing intratumoral infiltration of CD8+ T cells and macrophages, increasing IL-12 production, and increasing granzyme B production, resulting in improved immunogenicity in multiple tumor types [9, 10].

The final presented patient was a unique case of a patient with pleomorphic LMS who initially did not respond to single agent pembrolizumab. However, with the addition of ascorbate, the patient did show response. This further suggests immune enhancement by ascorbate when combined with an ICI in LMS. These data should be further evaluated in the context of a clinical trial. Additionally, further evaluation should be given for the use of pharmacological ascorbate with ICIs in other sarcoma subtypes, given limited treatment options for these patients and encouraging results demonstrated here. The CARE Checklist has been completed by the authors for this case report, attached as online supplementary material (for all online suppl. material, see https://doi.org/10.1159/000539979).

We present 3 patients with metastatic LMS – one each of soft tissue, vascular, and uterine origin. All 3 patients had a prolonged response to pembrolizumab with pharmacologic ascorbate. These encouraging data support investigation of pembrolizumab and pharmacological ascorbate in LMS.

The authors express their special thanks to Kristina Greiner for assistance with editing the final manuscript.

This study follows ethics guidelines, and consent from the patients was obtained prior to participation. This study protocol was reviewed, and the need for approval was waived by the Local IRB. Written informed consent was obtained from the patients for publication of the details of their medical case and any accompanying images.

The authors have no conflicts of interest to declare.

This study is supported by the University of Iowa Holden Comprehensive Cancer Center.

Study conceptualization and design: J.M.R. and M.L.M.; data collection and chart review: J.M.R. and A.C.B.; initial manuscript drafting: J.M.R., A.C.B., and M.L.W.; figure design: A.C.B.; and manuscript editing and revision: A.C.B., M.L.W., J.M.R., and M.M.M. All authors approved the final manuscript.

The data that support the findings of this study are not publicly available due to privacy reasons but are available on request. Further inquiries can be directed to the corresponding author.