VJVirtual | Overcoming sarcoma’s cold microenvironment with immunotherapy combinations

Considering the primary challenges that we are facing with immunotherapy in sarcomas, obviously one of them is the microenvironment. The microenvironment that is found in sarcoma is clearly called immunosuppressive with some very few exceptions, maybe 15% of angiosarcoma can have more than 20 mutations per DNA megabase, or some UPS, for instance, a proportion of 15% of UPS patients can exceed a larger number of mutations. But in general, the microenvironment is cold. So one of the strategies that have been used to overcome these resistances is the combination of anti-PD-1 or anti-PD-L1 compounds plus another type of compound that can be anti-angiogenic. For instance, this is the case of pembrolizumab plus axitinib or the case of sunitinib plus nivolumab or maybe the combination with double hit or double immune checkpoint inhibitors, which is the case of anti-CTLA4 plus anti-PD1, which is the case of ipilimumab plus nivolumab. So with these strategies, trying to inflame the cold microenvironment in sarcoma, it seems that the overall response rate is higher than just anti-PD-1 or anti-PD-L1, obviously by indirect comparison, and also the median of progression-free survival is longer than just monotherapy. This is obviously extrapolation and it’s difficult to compare studies because the inclusion criteria vary across different studies. So it’s difficult to draw conclusions, but the feeling of these studies is that probably the combination with anti-PD-1 or anti-PD-L1 plus anti-angiogenic or anti-CTLA4 is more convenient in terms of overall response rate and in terms at least of a longer progression-free survival. This is a good logical approach because the neoangiogenesis prevents the immune adaptive response. So blocking the neoangiogenesis can facilitate the role of the inhibitors of PD-1 or PD-L1 immune checkpoints. So another option, very topical issue, is the combination of chemotherapy based on anthracycline plus anti-PD-1 or anti-PD-L1. This is something relatively recent in the last two years, and recently have been published in JCO the experience of phase 1B with a combination of doxorubicin, dacarbazine, plus nivolumab in the context of first line of advanced leiomyosarcoma patients. So the overall response rate in this case was 56%, which is almost double than reported with the combination of doxorubicin, plus dacarbazine. and the median of progression-free survival was almost nine months, which by indirect comparison seems to be longer than just monotherapy. But it’s true that this scheme, this approach has one important vulnerability is that in the maintenance phase with just anti-PD-1, it seems to be not enough for disease control because the majority of progressions are seen in the early phase of maintenance with anti-PD-1 So we need to improve this phase. But in terms of overall response rate, it seems very, very powerful. And we will present this year in the ASCO meeting in the cohort of undifferentiated pleomorphic sarcoma. Also with this concept of chemoimmunotherapy with epirubicin, ifosfamide, plus nivolumab. and this will be also interesting to discuss in the context of the ASCO meeting. And last year, also in ASCO meeting, Chinese colleagues reported the experience of chemoimmunotherapy in other sarcoma subtypes, including UPS, but also the dedifferentiated liposarcoma and other subtypes. And again, the overall response rate was above 60%. So this strategy seems to be very, very powerful. And this seems to overcome the cold microenvironment in this context. And of note, in our team demonstrated that the HMGB1, which is a canonical biomarker of immunogenic cell death, increased over time in the prospective trial that I have mentioned of doxorubicin, dacarbazine plus nivolumab. And more importantly, the increase over one threshold was correlated with a longer progression-free survival. So it seems that this concept should be exploited in the upcoming comparative studies, and especially in the high-risk localized disease where chemoimmunotherapy plus radiation therapy, which can also add value for immunogenic cell death, maybe represent a qualitative jump in the cure of this subset of patients.