Abstract
Anti-PD-(L)1 therapies yield a disappointing response rate of 15% across soft-tissue sarcomas, even if some subtypes benefit more than others. The proportions of TAMs and TILs in their tumor microenvironment are variable, and this heterogeneity correlates to histotype. Tumors with a richer CD8+ T cell, M1 macrophage, and CD20+ cells infiltrate have a better prognosis than those infiltrated by M0/M2 macrophages and a high immune checkpoint protein expression. PD-L1 and CD8+ infiltrate seem correlated to response to immune checkpoint inhibitors (ICI), but tertiary lymphoid structures have the best predictive value and have been validated prospectively. Trials for combination therapies are ongoing and focus on the association of ICI with chemotherapy, achieving encouraging results especially with pembrolizumab and doxorubicin at an early stage, or ICI with antiangiogenics. A synergy with oncolytic viruses is seen and intratumoral talimogene laherpavec yields an impressive 35% ORR when associated to pembrolizumab. Adoptive cellular therapies are also of great interest in tumors with a high expression of cancer-testis antigens (CTA), such as synovial sarcomas or myxoid round cell liposarcomas with an ORR ranging from 20 to 50%. It seems crucial to adapt the design of clinical trials to histology. Leiomyosarcomas are characterized by complex genomics but are poorly infiltrated by immune cells and do not benefit from ICI. They should be tested with PIK3CA/AKT inhibition, IDO blockade, or treatments aiming at increasing antigenicity (radiotherapy, PARP inhibitors). DDLPS are more infiltrated and have higher PD-L1 expression, but responses to ICI remain variable across clinical studies. Combinations with MDM2 antagonists or CDK4/6 inhibitors may improve responses for DDLPS. UPS harbor the highest copy number alterations (CNA) and mutation rates, with a rich immune infiltrate containing TLS. They have a promising 15-40% ORR to ICI. Trials for ICB should focus on immune-high UPS. Association of ICI with FGFR inhibitors warrants further exploration in the immune-low group of UPS. Finally translocation-related sarcomas are heterogeneous, and although synovial sarcomas a poorly infiltrated and have a poor response rate to ICI, ASPS largely benefit from ICB monotherapy or its association with antiangiogenics agents. Targeting specific neoantigens through vaccine or adoptive cellular therapies is probably the most promising approach in synovial sarcomas.
Highlights
Immunotherapy of cancer has been the last major breakthrough in the fight against cancer [1, 2]
CDX1401 is a Dendritic cells (DCs) targeted antibody linked to NY-ESO-1 peptide, which has been combined with immune stimulating substances in a phase 1 trial of 45 patients including 5 sarcomas [164].This regimen allowed for stimulation of an NY-ESO-1 targeted response with no clinical responses but an interesting disease control rate (N=13/45) which lasted for a median of 6.7 months
Immune Microenvironment of LMS As we previously described, LMS is characterized by complex genomics with a high number of copy-number alterations (CNA), but a lower mutational burden than undifferentiated pleomorphic sarcomas (UPS) [64]
Summary
Immunotherapy of cancer has been the last major breakthrough in the fight against cancer [1, 2]. Some histotypes yield higher response rate, this regimen has an ORR of roughly 10% as monotherapy in an unselected population [31] but allows stabilisation of disease and a median PFS of 6 months in advanced setting [25, 26, 31]. In this light, it has been proposed that an active drug in STS yields a PFS rate of roughly 30-50% at six months in the first line and a PFS rate over 40% at three months in the second-line setting [32]. ICIs in the advanced setting in STS have consistently reported ORRs of roughly 15% with a median PFS around 3-4 months, when including all histotypes. In combination therapies (including other immune-based therapies or anti-angiogenic therapies), anti-PD1/anti-PDL1 were found to have an ORR of 13.4%
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