• Immune Checkpoint Inhibitor
• Immunotherapy
• Neoadjuvant
• Solid tumor

Soft tissue sarcomas (STSs) represent a group of heterogeneous malignant mesenchymal tumors, comprising 1% of all malignant tumors but with more than 100 histological types. Complete surgical resection is the cornerstone of sarcoma treatment for patients with resectable lesions. Unfortunately, a part of patients will experience relapse and metastasis after the surgery, mostly due to incomplete resection/positive resection margin or micrometastatic lesions that highlight the significance of neoadjuvant therapy. Neoadjuvant therapy serves several crucial purposes, including reducing tumor size, expanding the scope of resectability, and eliminating micrometastatic lesions. The role of neoadjuvant chemotherapy or radiation therapy (RT) has been demonstrated in sarcoma treatment. However, not all subtypes are sensitive to chemotherapy or RT, such as dedifferentiated liposarcoma (DDLPS) and alveolar soft part sarcomas (ASPS). Moreover, some patients missed the opportunity for surgery due to the side effects of chemotherapy or RT, suggesting other neoadjuvant treatment strategies deserve to be further explored.

Different from other solid tumors such as lung cancer and melanoma, the rarity of occurrence and variability of histological types pose challenges in conducting large clinical trials in STS. In this groundbreaking phase II clinical trial that Roland et al reported,1 17 patients with retroperitoneal DDLPS and 10 with extremity/truncal undifferentiated pleomorphic sarcoma (UPS) were categorized by subtypes and randomly assigned to receive either nivolumab monotherapy or nivolumab/ipilimumab combination therapy (patients with UPS also received concurrent RT), followed by surgical resection. The percentage of hyalinization at surgery as the primary endpoint of this trial was observed to be a median of 8.8% in DDLPS and 89% in UPS and was inversely proportional to the viable tumor (figure 1A). It is noteworthy that the ideal endpoint for pathological response after neoadjuvant therapy in sarcoma remains uncertain. In this study, the percentage of hyalinization other than necrosis was chosen because a few studies demonstrated that hyalinization was associated with relapse-free survival (RFS) after neoadjuvant RT in sarcomas, making it possible to consider hyalinization as an appropriate indicator of treatment response.2 3 The secondary endpoints, RFS at 24 months was 38% in DDLPS and 78% in UPS, while impressively, overall survival (OS) was 82% in DDLPS and 90% in UPS. In addition to this, SU2C-SARC032 (NCT03092323), a multicenter randomized phase II trial, is trying to evaluate the safety and efficacy of adding pembrolizumab to RT in the perioperative period for patients with stage III UPS or LPS4 (figure 1B). The results presented at ASCO 2024 showed that 2-year disease-free survival as the primary endpoint was significantly higher in the experimental arm (p=0.023; HR 0.57, 90% CI 0.35, 0.91), especially in patients with grade 3 sarcomas, demonstrating the advantage of combined immunotherapy. Furthermore, the NADINA trial in melanoma showed neoadjuvant and response-driven adjuvant ipilimumab plus nivolumab resulted in longer event-free survival than adjuvant one alone, with 120 patients achieving pCR/near pCR after neoadjuvant immunotherapy,5 underlining the superiority of neoadjuvant immunotherapy compared with adjuvant immunotherapy. In summary, these results highlight the positive treatment outcomes associated with neoadjuvant immunotherapy.

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Figure 1

Neoadjuvant immunotherapy in sarcomas. (A) The phase II clinical trial conducted by Roland et al, in which 17 patients with dedifferentiated liposarcoma (DDLPS) and 10 patients with undifferentiated pleomorphic sarcoma (UPS) were categorized by subtypes and randomly assigned to nivolumab group or nivolumab+ipilimumab group (UPS patients received radiation therapy concurrently). The primary endpoint is per cent hyalinization at surgery, observed in 17.6% of DDLPS patients (3/17) and 90% in UPS patients (9/10). (B) The trial timeline of SU2C-SARC032. Patients were randomly assigned to SOC arm (neoadjuvant RT) or EXP arm (neoadjuvant RT+pembrolizumab and adjuvant pembrolizumab). Pembrolizumab was given 200 mg once every 3 weeks for 3 doses during neoadjuvant therapy and up to 14 cycles during adjuvant therapy. (C) The changes in tumor microenvironment of sarcomas after neoadjuvant therapy, including increased CD4+T cells and M2 macrophage infiltration, increased B cells infiltration with suggestion of tertiary lymphatic structures, and enhanced antigen presentation, were associated with survival or treatment response. (D) The potential mechanism of hyper progressive diseases after adjuvant immunotherapy was reported by Li et al. T cell-derived IFNγ could stimulate the secretion of FGF2 in an autocrine way in tumor cells, followed by the phosphorylation of PKM2 that inhibited glycolysis in tumor so that NAD+levels was decreased, causing the acetylation of β-catenin and the activation of β-catenin signal pathway to promote tumor cells proliferation and stemness. Created with BioRender.com. EXP, experimental; FGF2, fibroblast growth factor 2; FGFR, fibroblast growth factor receptor; NAD, nicotinamide adenine dinucleotide; PKM2, pyruvate kinase isozyme type M2; RT, radiation therapy; SOC, standard of care.

However, two considerations are noteworthy. First, immunotherapy, once deemed promising for DDLPS, has shown limited efficacy in expansion cohorts and long-term follow-ups.6 Consistent with these findings, the response rate to neoadjuvant immunotherapy in DDLPS was also unsatisfactory. Second, the most compelling neoadjuvant immunotherapy data are with concurrent RT, and previous study suggests that neoadjuvant RT can enhance the immune response in sarcoma,3 underscoring the potential significance of concurrent RT in neoadjuvant immunotherapy. However, it is well known that DDLPS is not sensitive to RT, and whether neoadjuvant RT combined with immunotherapy can improve survival remains unknown. Therefore, it is essential to explore both the reasons for the disappointing response rate of immunotherapy in DDLPS, and the role of RT in neoadjuvant immunotherapy from both clinical trials and basic research perspectives.

In the phase II trial Roland et al reported1, patients whose tumors were with higher infiltration of cytotoxic T lymphocytes at baseline had better RFS, in contrast, higher baseline infiltration by Treg was associated with shorter RFS. Additionally, a higher density of Treg at baseline or on treatment was associated with absence of pathologic response. These results were consistent with a previous study that demonstrated the presence of Treg had a positive association with local recurrence in STS.7 The infiltration of B cells with tertiary lymphatic structures (TLS) features was increased after neoadjuvant immune checkpoint ihibitors (ICIs) treatment, in association with better OS in DDLPS. These findings echo earlier research that demonstrated patients with advanced STS featuring high expression of B cell genes and presence of TLS exhibited higher response to ICIs and improved survival.8 Previous studies demonstrated neoadjuvant RT in UPS, regardless of whether chemotherapy was combined, was promising in enhancing the immune response within the tumor microenvironment in STS, for increasing the density of tumor infiltrating immune cells including CD4⁺T cells and M2 macrophages, and upregulating genes and cytokines associated with antigen presentation that is pivotal for initiating an effective antitumor immune response.3 However, this study did not show an increased percentage of immune cell infiltration after neoadjuvant therapy with ICIs and RT in UPS, deserving further discussion and exploration.

For the moment, we are facing several challenges impeding the process of conducting neoadjuvant immunotherapy in sarcomas. First of all, not all types of sarcomas respond to immunotherapy. A study including 134 patients with advanced STS who were gathered from 4 clinical trials reported 5 subtypes had an objective response rate exceeded 30%, including angiosarcoma, myxofibrosarcoma, epithelioid sarcoma, UPS and ASPS.9 In short, ICIs have been widely studied in advanced STSs among different subtypes so far but the efficacy is relatively low in most of them. Selecting the appropriate subtypes of sarcoma patients for neoadjuvant immunotherapy remains a challenge, which emphasizes the need for further research on ICIs for STS and the importance of patient selection in optimizing treatment outcomes.

After that, a significant concern arises regarding the potential occurrence of hyperprogressive disease (HPD) with immunotherapy. The question of whether immunotherapy might trigger HPD warrants meticulous consideration. This concern stems from the abrupt nature of disease progression and the possibility of severe adverse effects associated with immunotherapy. 11% (15/134) of patients who were diagnosed with advanced STS and received ICIs experienced HPD in the study reported by Klemen et al, similar to the one in other solid tumors.9 The authors found that IFNα and IFNγ response pathways were elevated in HPD tumors compared with PD tumors. Recently, Li et al found that T cell-derived IFNγ could stimulate the autocrine of tumor fibroblast growth factor 2 in some tumor cells, which induced pyruvate kinase isozyme type M2 (PKM2) phosphorylation and then inhibited tumor glycolysis. The inhibition of glycolytic pathway decreased NAD⁺ levels, and further activated β-catenin acetylation and upregulated MYC and other genes to promote tumor stemness and tumorigenic potential.10 In summary, IFNγ-PKM2-β-catenin axis is essential for immunotherapy-associated HPD in patients with melanoma and non-small cell lung cancer (figure 1D). These results suggest that IFNγ may play an important role in HPD in patients with STS and is worthy of further exploration and research. In addition, specific gene expressions abnormalities, such as EGFR mutations and MDM2 amplifications, are intricately linked to the tumor immune microenvironment.11 These abnormalities can contribute to accelerated tumor growth in response to ICI therapy. It is noteworthy that over 90% of DDLPS patients carry MDM2 amplifications.12 Given these risks, accurately identifying the population of sarcoma patients who would benefit from neoadjuvant immunotherapy becomes crucial. The search for reliable biomarkers has become a focal point in the development of immunotherapy. Using biomarkers involves not only identifying patients who may benefit from treatment but also excluding those at a higher risk of HPD during treatment. Unfortunately, current tumor biomarkers widely used in advanced-stage patients, including PD-L1 expression levels and tumor mutational burden, remain a subject of debate in the context of neoadjuvant immunotherapy. These biomarkers have not yet been conclusively validated in the assessment of neoadjuvant treatment efficacy. Therefore, it is imperative to prioritize the exclusion of patients who are unlikely to benefit from ICIs and, in some cases, may even experience disease progression. Methods such as next-generation sequencing help identify driver genes that may not confer benefits from ICIs. Additionally, collaboration among multidisciplinary teams, with alert and clinical expertize, is essential to promptly detect potential cases of HPD and minimize treatment delays.

And then, optimizing clinical treatment decisions both preoperatively and postoperatively remains an area of ongoing exploration. This includes determining the ideal cycles of treatment, the treatment regimen (single agent or combination), and postoperative clinical management. Based on the current available data, most studies in other solid tumors employ 2–6 cycles of neoadjuvant immunotherapy before surgery. However, this strategy lacks robust evidence from clinical trials, and it remains unclear whether administering more treatment cycles correlates with improved prognosis. It is recommended to reevaluate patients after two cycles of treatment and adjust the treatment plan based on the assessment results. Further research is needed to establish evidence-based guidelines for optimizing treatment duration and strategies in both the preoperative and postoperative phases of sarcoma management.

In summary, the goal of neoadjuvant immunotherapy is to prolong survival and increase the cure rate of patients by providing long-term immunity against the tumor. It is crucial to prioritize the careful selection of individuals who are likely to benefit from this treatment approach. Additionally, there is a need for exploration into combined neoadjuvant strategies and further research into efficacy biomarkers and alternative biomarkers. We have summarized the currently registered studies in online supplemental table 1. Neoadjuvant immunotherapy faces significant challenges in sarcoma treatment, but we are full of expectations for its future.