Cure Alveolar Soft Part Sarcoma International (iCureASPS)

Abstract
The fifth “Melanoma Bridge Meeting” took place in Naples, December 1–5th, 2015. The main topics discussed at this meeting were: Molecular and Immuno advances, Immunotherapies and Combination Therapies, Tumor Microenvironment and Biomarkers and Immunoscore. The natural history of cancer involves interactions between the tumor and the immune system of the host. The immune infiltration at the tumor site may be indicative of host response. Significant correlations were shown between the levels of immune cell infiltration in tumors and patient’s clinical outcome. Moreover, incredible progress comes from the discovery of mutation-encoded tumor neoantigens. In fact, as tumors grow, they acquire mutations that are able to influence the response of patients to immune checkpoint inhibitors. It has been demonstrated that sensitivity to PD-1 and CTLA-4 blockade in patients with advanced NSCLC and melanoma was enhanced in tumors enriched for clonal neoantigens. The road ahead is still very long, but the knowledge of the mechanisms of immune escape, the study of tumor neo-antigens as well as of tumor microenvironment and the development of new immunotherapy strategies, will make cancer a more and more treatable disease.
https://translational-medicine.biomedce ... 016-1029-z

Background
Because cancer is a heterogeneous and dynamic microenvironment communicating with the immune system, the immune contexture of tumor microenvironment showed to be able influence the course of the disease. Hence, pre-existing immunity is determining the fate and survival of the patient and the likelihood of response to immunotherapy.

Quantification of immune cell densities (n = 415 patients, 6640 immunostains) revealed the major positive role of cytotoxic and memory T cells for patient’s survival [1]. These findings became the foundation of a new concept: immune contexture (i.e. nature, functional orientation, density, and location within distinct tumor regions, of a natural in situ immune reaction) might be used by immunoscore. Recently, many reports suggest that cancer development is controlled by the host’s immune system underlying the importance of including immunological biomarkers for the prediction of prognosis and response to therapy. For this reason, the impact of the immunoscore needs to be evaluated more thoroughly in other tumor types given the universal importance of the immune system in cancers.

Update on Immunoscore Worldwide Consortium (SITC) and Immunoscore on other cancer types
Immunoscore in colorectal cancer
The Immunoscore is now defined as a prognostic tool to use for quantification of in situ immune cell infiltrates, which appears to be superior to the tumor-node-metastasis (TNM) classification in colorectal cancer. In NSCLC, no Immunoscore has been established, but in situ tumor immunology is recognized as highly important [2]. The question still open is the challenge of the “universal” character of the Immunoscore.

In 2006 it was demonstrated that the immunological data (the type, density, and location of immune cells within the tumor samples) are a better predictor of patient survival than the histopathological methods currently used to stage colorectal cancer. An international consortium has been initiated to validate and promote the Immunoscore in routine clinical settings [3]. Specifically, an Immunoscore based on the combined analysis of CD8+ plus CD45RO+ cells in specific tumor regions was a useful criterion for the prediction of tumor recurrence and survival in patients with early-stage (AJCC/UICC-TNM stages I and II) CRC. Also, when considering the disease-specific survival according to CD8+ and CD45RO+ densities in combined tumor regions (central tumor/invasive margin, CT/IM), the scoring system allows to identify subgroups of patients with distinct clinical outcomes in terms of disease-free survival and overall survival [4]. The importance of the localized immune reaction in predicting recurrence and survival in patients with early-stage colorectal carcinoma has also been assessed [5].

Immunoscore in melanoma
Immune-regulated pathways influence multiple aspects of tumor development and present multiple opportunities to gage its response in order to make treatment decisions regarding: (1) prognosis (the presence of the right immune effector cells is correlated with better prognosis and survival) (2) immunotherapy (manipulate the patient’s own immune system to respond to the tumor) and (3) chemotherapy (response may also be immune-related).

The definition of Immunoscore in melanoma, based on the complex intratumoral immune reaction, is becoming a difficult challenge. So far the value of the Immunoscore has been well established in patients with early-stage (stage I–II) colorectal cancer where the immune profile seems have higher prognostic importance than clinical features such as TNM-staging system [5].

The Immunoscore is evaluated in metastatic lymph node tissue because they represent an extremely interesting model for a number of reasons as it has jet been demonstrated: for adjuvant therapy (melanoma stage III), they are more accessible than visceral metastases and the risk for distant metastases is high, and at last [12–14]. Patients with a stage III disease can benefit from an adjuvant therapy (interferon, immunotherapy), in fact, the evaluation of the microenvironment in the lymph nodes could be important for patient selection, and In many cases, the metastatic lymph nodes from lymphectomy are the only available tissue.

On the other hand, concerns are raised about the Immunoscore in lymph nodes because they are constitutively rich in CD3 and CD20 lymphocytes and, also, the evaluation of the periphery of the tumor is particularly complex. Moreover, lymph node metastases may be different in terms of immune infiltration compared to other metastatic lesions. Clinical outcome and prognostic factors of superficial and deep lymph node dissection for stage III cutaneous melanoma were retrospectively studied in patients who underwent surgical lymph node dissection for metastases at the National Cancer Institute, Naples. One of the aims was to develop an algorithm for the evaluation of the different markers [15]. In the cell counts for each patient, no apparent differences were found in expression levels in the reactive lymph nodes between relapse and no relapse groups, except for CD8, in which there were more patients with high expressing cells in the relapse group. There were significant differences in the peri/intra ratio for both CD3 and CD8, with the ratio being higher in no relapse patients compared to relapse patients for both proteins. Similar differences were seen in FoxP3 and CD20. These preliminary data were used to develop a risk score currently investigated in a larger melanoma cohort. The algorithm was developed using the whole slide images from serial sections stained with different markers that were automatically identified from tumor marker slide. Region labels were then transferred to marker slides via image registration and cells were automatically counted for each region. The report of cell counts and region labels for each patient was analyzed in the onco-immune report [16].

In order to investigate the predictive power of Immunoscore, the MISIPI study has involved 200 FPFE samples from metastatic melanoma patients treated with Ipilimumab where density of different immune populations was assessed, using a digital image analysis application to characterize immune infiltrate expression of CD3, CD8, CD20, FoxP3 and CD163 and of PD-L1. The aim was to correlate marker expression profile with clinical outcome [17]. No relationship between CD3, CD8, CD20, CD163, FoxP3 both intratumoral (CT) and peritumoral (IM) with response/benefit was evidenced, but only a trend for the CD163 positive PD-L1 positive (CT) population (p = 0.07). CD8+ PD-L1− and higher and lower than median at IM seems to correlate with OS (p = 0.04). A similar correlation was found for CD163+ PD-L1+ (p = 0.05). The conjugated analysis presented even better correlation with overall survival (OS) (p = 0.01).

In the same time, a proof-of-concept study was designed with 31 patients (11 CR, 1 PR, 4 SD and 15 PD) on first line treatment with cisplatin + temodal or dacarbazine or other. Tissue sections were stained with H&E, CD3 and FoxP3. Co-expression analysis was performed on the basis of an automated alignment of serial sections in order to correlate cell density patterns with Ipilimumab patient OS. First results indicate that melanocyte-FoxP3 spatial relations are the most predictive factors and that, while CD3 alone does not provide substantial value, CD3/FoxP3 ratio on IM seems to be a promising additional factor.

Facts and Hopes in Immunotherapy of Soft-Tissue Sarcomas

Sarcomas are mesenchymal tumors, encompassing more than 175 subtypes, each one with their own genetic complexities. As a result, immunotherapy approaches have not been universally successful across the wide range of diverse subtypes. The actual state of science and the current clinical data utilizing immunotherapy within the soft-tissue sarcomas (STS) will be detailed in this review. More precisely, the review will focus on: (i) the role of the immune microenvironment in the development and activity of new therapeutic approaches; (ii) the recent identification of the sarcoma immune class (SIC) groups, especially group SIC E with its B-cell signature that predicts immunotherapy response; (iii) the clinical trials using PD-1 and/or CTLA-4 inhibitors, which serves as reference for response data, (iv) the promising clinical activity from the combination of anti-angiogenics agents with PD-1 inhibitors, (v) the adapted T-cell therapies for synovial sarcoma that target either NY-ESO or MAGEA4; and (vi) the role for localized therapy using the virotherapy T-VEC with PD-1 inhibitors. Herein, we present the facts and the hopes for the patients with sarcoma, as the field is rapidly advancing its understanding of what and where to use the various types of immunotherapies.

Combination therapies with immune checkpoint inhibitors
Because of poor results observed with monotherapy, investigators have explored combinations for a more efficient immunomodulation, trying to convert the sarcoma microenvironment into T-cell–inflamed tumor. Alliance A091401 is the only reported randomized trial testing nivolumab alone against ipilimumab and nivolumab in STS. There were six objective responses of 38 evaluable patients (16%; 92% CI, 7–30) in the combination arm. Responses were seen in UPS (2), leiomyosarcoma (2), angiosarcoma (1), and myxofibrosarcoma (1). The mPFS was 4.1 months (95% CI, 2.6–4.7) and the mOS was 14.3 months (95% CI, 9.6–not reached; ref. 38).
Angiogenesis mediators as VEGFA have a well-known function promoting neoangiogenesis, while preventing immune response (39). A phase II clinical trial examining axitinib 5 mg twice daily with pembrolizumab 200 mg starting on day 8 and then every 3 weeks was investigated in 33 patients with STS. There were 69% of patients with at least two previous lines, 51% that had received previous tyrosine kinase inhibitors, and 36% diagnosed with alveolar soft-part sarcomas (ASPS). The endpoint was 3-month PFS rate of 40%. The 3-month and 6-month PFS rates were 65.6% (95% CI, 46.6–79.3) and 46.9% (95% CI, 29.2–62.8), respectively. Of 32 evaluable patients, 8 (25%) had partial response and 9 (28%) had stable disease. Six responders were ASPS, one was epithelioid sarcoma, and another was leiomyosarcoma. The median duration of response was 29 weeks, while the mOS was 18.7 months. Neither PD-L1 positivity nor high TIL showed statistical correlation with PFS or partial response. Interestingly, angiogenic plasmatic activity at baseline was more likely to respond to this regimen (40). Intriguingly, ASPS seems to be sensitive to immunotherapy-based regimens, even if this histologic subtype does not exhibit an immune-sensitive microenvironment. In fact, it has been reported that ASPS has a TIL ratio lower than nontranslocation-related sarcomas (20) and the TMB is also lower compared with other histologic subtypes, such as synovial sarcoma or Ewing sarcoma (41). In this latter study, a MMR deficiency signature was associated with the activity of anti-PD-L1 in ASPS, however, further studies in larger series of cases are required to validate these observations.

https://aacrjournals.org/clincancerres/ ... oft-Tissue


* http://www.cureasps.org/forum/viewtopic ... 709#p10709