Biological Rationale Explained for Continued Investigation of Immunotherapy in Sarcomas

William D. Tap, MD

There is a biological rationale for the exploration of immunotherapeutics in sarcomas, but more work needs to be done to build upon the understanding of the immunotherapeutic potential of these tumors, according to William D. Tap, MD.

Tap, chief of the Sarcoma Medical Oncology Service at Memorial Sloan Kettering Cancer Center, discussed the role for immunotherapy in patients with soft tissue sarcomas and gastrointestinal stromal tumors (GISTs) during a presentation at the 2018 ESMO Sarcoma & GIST Symposium. In the sarcoma field, the potential benefit of immunotherapy is currently challenged not only by the heterogeneity of each patient, but also by the heterogeneity of each histologic subtype.

Early studies of immunotherapy in patients with sarcoma often receive criticism because they included too many histologic subtypes of sarcomas, for example. Although the benefit of single-agent immunotherapies has historically been modest, Tap highlighted the biologic rationale of the use of immunotherapy in sarcomas and ways that these responses could be boosted with combinations currently under investigation.

“We look at what other diseases are using for predictive biomarkers, and to predict responses, all of these, from immune infiltrates to aneuploidy to PD-L1 expression to mutational burden, all play a role in sarcoma. The questions are, can we determine which ones in which patients, and is there a unified way to approach this?” Tap said.

Various trials have shown differing amounts of PD-L1 expression across sarcoma subtypes, ranging from 12% in one study to 65% in another, with key differences found between where the PD-L1 expression was noted. In one such study of 50 patients with sarcoma, tumor cell PD-L1 expression was observed in 12% of cases, lymphocyte PD-L1 expression in 30%, and macrophage PD-L1 expression in 58%. The highest frequency of PD-L1 expression was noted in GISTs. On the other hand, lymphocyte and macrophage infiltration were identified in 98% and 90% of cases, respectively.1

The majority of sarcomas do not have a high tumor mutational burden, Tap said, but approximately 5% of patients with sarco- mas do have a high mutational burden, according to an analysis of next-generation sequencing in thousands of patients with sarcomas.²There was a wide distribution across the sarcoma subtypes, however, of patients with a high mutational burden.

“How do we actually begin to look at these datasets to create a foundation of what [are] the different aspects of the immune system that [are] activated in sarcoma, what are the potential immune infiltrates that we’re seeing and in what subtypes, and what may be some potential signs of innate resistance that these tumor cells have? The more we can develop the foundation...the more we’ll be able to understand the response patterns that we see,” Tap urged.

Another aspect of the immune microenvironment that was highlighted by Tap was macrophages, as he noted that many sarcomas, especially those that may be resistant to single-agent checkpoint inhibition, may have a significant infiltrate of M2 macrophages, which also correlates with a worse prognosis.

A phase II clinical trial of pembrolizumab (Keytruda), a PD-1 checkpoint inhibitor, in combination with low-dose cyclophosphamide demonstrated that the majority of patients in the study had strong infiltration by M2 macrophages expressing indoleamine 2,3-dioxygenase (IDO).3 The study authors noted, and Tap reiterated, that this increased infiltra- tion suggests an innate resistance and supports the further study of anti—PD-1/PD-L1 therapy in combination with IDO inhibitors and/or CSF-1R inhibitors in patients with sarcomas.

Combination approaches with immunotherapy are increasingly being investigated in studies of patients with sarcoma. Tap first pointed to the combination of nivolumab (Opdivo) and ipilimumab (Yervoy) in patients with metastatic sarco- mas. Patients treated with nivolumab alone had an objective response rate (ORR) of 3%, with partial responses seen in a patient with alveolar soft part sarcoma, one with leiomyosarcoma, and one with an unspecified sarcoma. The addition of ipilimumab led to an increased amount of responses with an ORR of 16%. Two complete responses were observed, one in a patient with myxofibrosarcoma and another in a patient with uterine leiomyosarcoma.⁴

“Maybe combination therapies are broadening [the] potential types of responses that we’re seeing. Combination therapies may be doing something to the immune microenvironment, may be helping to overcome innate resistance, may be doing something to prime immune responses,” he commented.

Tap drew attention to a number of ongoing studies that are looking at ways to enhance responses to immunotherapy in sarcomas. One study is exploring the use of nivolumab in combination with NKTR-214 to turn cold tumors hot in patients with locally advanced or metastatic high-grade sarcoma in a phase II pilot trial (NCT03282344). Another phase II study is investigating modulating the immune microenvironment with talimogene laherparepvec in patients with locally advanced or metastatic sarcoma in combination with pembrolizumab for a potential abscopal effect (NCT03069378). Additionally, radiation is being studied in combination with pembrolizumab in a phase II study in patients with high-risk soft tissue sarcoma of the extremity (NCT03092323), as immune effectors can be increased with radiation and immune suppressors are typically upregulated in sarcomas.

These clinical studies will help to suggest strategies to improve responses to immunotherapy in sarcoma, but Tap advocated for the use of increased clinical correlates and more biomarker analyses in these and other studies in order to look at what happens to the immune microenvironment in sarcomas before and after treatment.

References:

1. D’Angelo SP, Shoushtari AN, Agaram NP, et al. Prevalence of tumor-in ltrating lymphocytes and PD-L1 expression in the soft tissue sarcoma microenvironment. Hum Pathol. 2015;46(3):357-365. doi: 10.1016/j.humpath.2014.11.001.
2. Gounder MM, Ali SM, Robinson V, et al. Impact of next-generation sequencing (NGS) on diagnostic and therapeutic options in soft-tissue and bone sarcoma. J Clin Oncol. 2017;35(suppl; abstr 11001). meetinglibrary.asco.org/record/153364/abstract.
3. Toulmonde M, Penel N, Adam J, et al. Use of PD-1 targeting, macrophage in ltration, and IDO path- way activation in sarcomas. JAMA Oncol. 2018;4(1):93-97. doi: 10.1001/jamaoncol.2017.1617.
4. D’Angelo SP, Mahoney MR, Van Tine BA, et al. A multi-center phase II study of nivolumab +/- ipili- mumab for patients with metastatic sarcoma (Alliance A091401). J Clin Oncol. 2017;35(suppl; abstr 11007). meetinglibrary.asco.org/record/145287/abstract.