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Despite being one of the first types of cancers studied that hinted at a major role of the immune system in pro- and anti-tumor biology, little is known about the immune microenvironment in sarcoma. Few types of sarcoma have shown major responses to immunotherapy, and its rarity and heterogeneity makes it challenging to study. With limited systemic treatment options, further understanding of the underlying mechanisms in sarcoma immunity may prove crucial in advancing sarcoma care. While great strides have been made in the field of immunotherapy over the last few decades, most of these efforts have focused on harnessing the T cell response, with little attention on the role B cells may play in the tumor microenvironment. A growing body of evidence suggests that B cells have both pro- and anti-tumoral effects in a large variety of cancers, and in the age of bioinformatics and multi-omic analysis, the complexity of the humoral response is just being appreciated. This review explores what is currently known about the role of B cells in sarcoma, including understanding the various B cell populations associated with sarcoma, the organization of intra-tumoral B cells in tertiary lymphoid structures, recent trials in immunotherapy in sarcoma, intra-tumoral immunoglobulin, the pro-tumor effects of B cells, and exciting future areas for research.

An ambiguous pathologic report can present a clinical dilemma to the treating surgeon. We describe lesions ranging from the potentially benign to the likely malignant. Correctly identifying features associated with higher-risk lesions has proven challenging given the overall good prognosis and low rate of events. An appropriate treatment plan generally requires discussion between the surgeon and an experienced dermatopathologist. When clinically indicated, additional testing may be used to further support or refute a diagnosis of melanoma. The indications for these techniques, the data to support their use, and the strengths and weakness of each are reviewed.

PURPOSE Response to programmed cell death protein 1 (PD-1) blockade is often conceptualized as resulting from reinvigoration of tumor-infiltrating lymphocytes. However, recruited antitumor immunity from the periphery may also be an important contributor to response. A detailed assessment of the response dynamics of individual metastasis could provide insight to the systemic and local features that mediate response and resistance to immunotherapy. MATERIALS AND METHODS Patients with metastatic non–small-cell lung cancer (NSCLC) or mismatch repair deficiency (MMRD) carcinoma treated with PD-1 monotherapy were evaluated independently. Absolute and percent change of each target lesion were quantified at each computed tomography scan using RECIST. Patterns of progression were predefined as systemic or mixed and were correlated with clinical outcomes. RESULTS A total of 761 individual lesions from 214 patients with NSCLC and 290 lesions from 78 patients with MMRD carcinoma were examined. Individual target lesion responses aligned with best overall response of each patient (85% NSCLC and 93% MMRD lesions responded in patients with partial response/complete response). In responding patients, timing of response was uniform (73% NSCLC and 76% MMRD lesions responded synchronously), and deeper responses were associated with prolonged progression-free survival and overall survival. By contrast, at progression, mixed progression was common (45% of NSCLC and 53% of MMRD) and associated with improved survival compared with those who experienced systemic progression (NSCLC hazard ratio [HR], 0.58; P = .001; MMRD HR, 0.40; P = .07). Organ sites had differential responses, with lymph node and liver metastasis among the most and least responsive, respectively. CONCLUSION Temporal-spatial patterns of response across individual metastases tend to be uniform, favoring the role of peripheral, clonally directed antitumor immunity as a key mediator of response to PD-1 blockade. In contrast, progression is more heterogeneous, potentially revealing the clinical importance of local features and intertumoral heterogeneity.

Purpose/Objective(s) Preoperative radiation therapy (RT) is an integral component of local control in soft tissue sarcoma (STS), but the conventional 5-week treatment course is burdensome for patients (pts). We conducted a single-institution phase 2 study of 5-day dose-equivalent preoperative RT for high-risk primary STS, which demonstrated acceptable rates of wound complications and 2-year toxicity. Here, we present results with longer follow-up, including additional pts from an expansion cohort. Materials/Methods The initial cohort accrued between April 2016 and May 2018 and included 52 pts with histologically confirmed extremity or trunk STS planning to undergo preoperative RT followed by surgery. The primary endpoint of the initial cohort was the rate of grade ≥2 radiation morbidity (fibrosis, lymphedema, or joint stiffness) at 2-years. An expansion cohort opened in October 2018 to compare wound complication rates between preoperative RT alone versus chemoRT and has enrolled an additional 47 pts. Patients received 30 Gy (RT alone) or 25 Gy (chemoRT) over 5 daily fractions to the primary tumor with standard margins. Here we report on pts with primary localized STS who completed preoperative RT and surgery in the initial and expansion cohorts (N = 79; chemoRT excluded). We assessed disease outcomes (local control, distant metastasis, and survival rates) and toxicity (grade ≥2 fibrosis, lymphedema, or joint stiffness) after minimum 2-year follow-up (N = 52). Fibrosis and joint stiffness were graded using RTOG/EORTC criteria, and lymphedema by Stern's scale. We also updated the major wound complication rate (defined per established criteria) after minimum 1-year follow up (N = 60). Results Of the 52 pts with minimum 2-year follow-up, predominant histologic subtypes included undifferentiated pleomorphic sarcoma, spindle cell sarcoma or sarcoma NOS (N = 24), myxofibrosarcoma (N = 8), and myxoid liposarcoma (N = 12). Median tumor size was 6.9 cm, and 15 pts had tumors ≥10 cm. At a median follow-up of 3 years, the local recurrence, distant metastasis and all-cause mortality rates were 6.5% (3 of 46 evaluable pts), 20.8% (10 of 48 evaluable pts), and 21.2% (11 of 52). Two of 3 pts (66%) with a local recurrence had undergone R1 resections, compared to 9 of 46 (19.5%) overall. The rate of overall grade ≥2 radiation morbidity in this same group was 13.0% (fibrosis: 5 pts, joint stiffness: 5 pts, lymphedema: 2 pts). Major wound complications were observed in 16 out of 60 (26.7%) evaluable pts. Conclusion Longer follow-up of a phase 2 study of 5-day pre-operative RT for pts with extremity/trunk STS demonstrates excellent local control. Rates of radiation fibrosis, joint stiffness and lymphedema, as well as wound complications, remain acceptable. We have also developed a web-based, interactive user interface for data visualization, which can help providers identify and understand relationships between baseline characteristics and clinical outcomes in our study.

Purpose Given the diverse and aggressive nature of soft tissue sarcomas (STSs), a need exists for more-precise therapy. Patient-derived orthotopic xenografts (PDOXs) provide a unique platform for personalized treatment. Thus, identification of patient and treatment factors that predict PDOX establishment is important. This study assessed the feasibility of incorporating PDOXs into the clinical setting and identifying factors associated with PDOX establishment. Patients and Methods From May 2015 to May 2016, 107 patients with biopsy-proven or potential STS were enrolled. Tumor samples were obtained intraoperatively and orthotopically implanted into nude mice in the corresponding anatomic location. PDOXs were considered established after engraftment and serial passage. Factors associated with establishment were analyzed by logistic regression and time to establishment by time-to-event analysis. Results Only high-grade tumors established (32 of 72 [44.4%]). The establishment rate (ER) varied by neoadjuvant therapy and treatment response, with the highest ER among untreated high-grade tumors (26 of 42 [61.9%]). Tumors exposed to radiation preoperatively did not establish (zero of 11 [0%]), and tumors exposed to neoadjuvant chemotherapy had a lower ER (31.9%) than untreated tumors. Only STSs with minimal pathologic response to neoadjuvant treatment (≤ 30%) established a PDOX (six of 18 [33.3%]). Median establishment time was 54 days, which varied by neoadjuvant therapy but was not statistically significant ( P = .180). Conclusion To our knowledge, in the largest STS PDOX study to date, we demonstrate a 62% ER among untreated high-grade tumors with a median establishment time of 54 days. Neoadjuvant therapy, particularly radiation, and pathologic response to treatment were associated with a reduced rate of PDOX establishment.

Background: BO-112 is a double stranded synthetic RNA formulated with polyethyleneimine. By mimicking a viral infection, it mobilizes the immune system, including activation of dendritic cells, CD8 T-cell infiltration, induction of interferons, and enhancement of immunogenic cell death. Intratumoral (IT) BO-112 has been tested both alone and in combination with anti-PD-1 therapies in a phase I trial (NCT02828098), which showed an overall response rate (ORR) of 11% and disease control rate (DCR) of 46% in patients with multiple tumor types and a tolerable safety profile. While anti-PD1 therapies have shown promise in select subtypes of soft tissue sarcoma (STS), their overall efficacy in STS has been limited. We hypothesize that BO-112, in combination with radiotherapy (RT), may reverse resistance to anti-PD1 therapy in a subset of patients with STS. Methods: This is an exploratory phase I study of IT BO-112 in combination with nivolumab in patients with STS planning to undergo neoadjuvant RT (NCT04420975) and surgery. BO-112 at a dose of 1 mg will be administered intratumorally on days 1, 8 and 15; nivolumab 240 mg will be administered intravenously on days 8 and 22. Patients will receive 5 fractions of neoadjuvant RT between day 8 and 12, followed by surgical resection between days 26 and 50. Twenty patients with newly diagnosed high grade histologically confirmed STS of the extremity, trunk or retroperitoneum amenable for IT injection will be included. Allowed histological subtypes are undifferentiated pleomorphic sarcoma, myxofibrosarcoma, leiomyosarcoma, dedifferentiated liposarcoma and synovial sarcoma.The primary objective is to explore the safety of BO-112 in combination with nivolumab in patients undergoing preoperative RT. The study includes stopping rules based on the frequency of dose limiting toxicities. As an exploratory single arm pilot study results will be reported using purely descriptive statistics. Tumor and blood specimens collected at baseline, at each IT BO-112 injection, and surgery will allow evaluation of the dynamic changes in tumor immune infiltration, T cell receptor repertoire, and tumor necrosis. These dynamic changes, along with putative biomarkers, such as baseline tumor mutational load, copy number alterations, tumor immune composition, tumor and immune gene expression signatures, and PD-L1 expression, will be related to individual subject tumor responses. The 2-year rate of local recurrence and distant metastasis will also be assessed. This study began accrual in December 2020 and is open. Citation Format: Anusha Kalbasi, Fritz C. Eilber, Arun Singh, Bartosz Chmielowski, Nicholas Bernthal, Brooke Crawford, Joseph G. Crompton, Varand Ghazikhanian, Leanne Seeger, Kambiz Motamedi, Michael L. Douek, Carol Felix, Vincent Basehart, Helena Escuin-Ordinas, Marisol Quintero, Sonia Macia. A phase I study of intratumoral BO-112 and nivolumab for resectable soft tissue sarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT221.

11546 Background: Surveillance imaging of patients with retroperitoneal liposarcoma (RP-LPS) following surgical resection is based on a projected risk of locoregional and distant recurrence. The duration of surveillance is not well defined as the long-term natural history of RP-LPS after treatment is poorly understood. We evaluate a cohort of RP-LPS patients—without evidence of disease 10 years following initial resection—to assess the long-term risk of recurrence and disease-specific survival (DSS). Methods: The prospectively maintained UCLA Sarcoma Database was used to identify RP-LPS patients who demonstrated 10-year progression-free survival (10yr-PFS) after initial diagnosis and treatment. Patients in the 10yr-PFS cohort were subsequently evaluated for recurrence and DSS. Time intervals start at date of initial surgical resection. Cox proportional hazards models were used to determine factors associated with recurrence and DSS. Results: From 1972-2010, 76 patients with RP-LPS had at least 10 years of follow-up. Of these, 37 (49%) demonstrated 10yr-PFS. Median follow-up was 15 years (range 10-35 years). Among the 10yr-PFS patients, 43% (16/37) developed a recurrence >10 years after the initial surgery, and 19% (7/37) died of disease. Neither long-term recurrence nor DSS were significantly associated with age, sex, tumor size, LPS subtype, surgical margin, or peri-operative treatment with radiation or chemotherapy (Table). Conclusions: Patients with primary RP-LPS treated with surgical resection +/- multimodality therapy have a long-term risk of recurrence and disease-specific death that is unacknowledged by current surveillance imaging guidelines. Among the patients with a 10yr-PFS, 43% developed a recurrence and 19% died of disease. These findings suggest a need for lifelong surveillance imaging in patients with RP-LPS.[Table: see text]

Although immunosuppression has been a key component to the success of solid-organ transplantation, the morbidity associated with long-term immunosuppression remains a substantial burden, particularly as recipients of transplants live longer. Indeed, malignancy is one of the most common reasons for mortality following transplantation and the most common of these cancers are cutaneous in origin. Recently, the incidence of these malignancies has been on the rise, partly due to the fact that recipients of these transplants are living longer as a result of improvements in surgical technique, immunosuppression and perioperative management. Although there have been initiatives to increase awareness of cutaneous malignancies following transplantation, such programs are not standardized and there continues to be gaps in skin cancer education and post-operative surveillance. This review provides an update on the epidemiology, risk factors, clinical management, prevention and surveillance of cutaneous malignancies.

The new edition of the American Joint Committee on Cancer staging system for melanoma builds on the foundation of prior editions but has several important improvements. The availability of regional nodal staging using sentinel lymph node biopsy (with subsequent follow-up) has resulted in more accurate prognostication for patients and clinicians. This facilitates identification of those at higher risk for recurrence, and allows for the appropriate selection of patients for new adjuvant therapy and clinical trials. Although more complex than previous editions, the eighth edition will provide granularity to outcome analysis based on more precise risk stratification.

Sarcomas of soft tissue and bone are mesenchymal malignancies that can arise in any anatomic location, most commonly the extremity, retroperitoneum, and trunk. Even for lower grade histologic subtypes, local recurrence can cause significant morbidity and even disease-related death. Although surgery remains the cornerstone of local control, perioperative radiation and systemic therapy are often important adjuvants. This review will summarize the current therapeutic approaches for local control of soft tissue and bone sarcomas.

Adoptive cell therapy (ACT) using autologous tumor-infiltrating lymphocytes (TIL) results in complete regression of advanced cancer in some patients, but the efficacy of this potentially curative therapy may be limited by poor persistence of TIL after adoptive transfer. Pharmacologic inhibition of the serine/threonine kinase Akt has recently been shown to promote immunologic memory in virus-specific murine models, but whether this approach enhances features of memory (e.g., long-term persistence) in TIL that are characteristically exhausted and senescent is not established. Here, we show that pharmacologic inhibition of Akt enables expansion of TIL with the transcriptional, metabolic, and functional properties characteristic of memory T cells. Consequently, Akt inhibition results in enhanced persistence of TIL after adoptive transfer into an immunodeficient animal model and augments antitumor immunity of CD8 T cells in a mouse model of cell-based immunotherapy. Pharmacologic inhibition of Akt represents a novel immunometabolomic approach to enhance the persistence of antitumor T cells and improve the efficacy of cell-based immunotherapy for metastatic cancer. Cancer Res; 75(2); 296–305. ©2014 AACR.

// Elizabeth Shurell 1, * , Arun S. Singh 2, 7, * , Joseph G. Crompton 1 , Sarah Jensen 2 , Yunfeng Li 3 , Sarah Dry 3, 7 , Scott Nelson 3, 7 , Bartosz Chmielowski 2, 7 , Nicholas Bernthal 4, 7 , Noah Federman 2, 7 , Paul Tumeh 5, 7 , Fritz C. Eilber 1, 6, 7 1 Division of Surgical Oncology, Department of Surgery, University of California, Los Angeles, CA 90095, USA 2 Department of Hematology/Oncology, University of California, Los Angeles, CA 90095, USA 3 Department of Pathology and Laboratory Medicine, University of California, Los Angeles, CA 90095, USA 4 Department of Orthopaedic Surgery, University of California, Los Angeles, CA 90095, USA 5 Department of Dermatology, University of California, Los Angeles, CA 90095, USA 6 Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095, USA 7 UCLA JCCC Sarcoma Program, University of California, Los Angeles, CA 90095, USA * indicates co-first authors Correspondence to: Fritz C. Eilber, email: fceilber@mednet.ucla.edu Keywords: immune microenvironment, MPNST, PD-L1, CD8, sarcoma Received: June 29, 2016 Accepted: August 16, 2016 Published: August 31, 2016 ABSTRACT Background: Malignant peripheral nerve sheath tumor (MPNST) is an aggressive sarcoma with few treatment options. Tumor immune state has not been characterized in MPNST, and is important in determining response to immune checkpoint blockade. Our aim was to evaluate the expression of programmed death-ligand 1 (PD-L1), programmed cell death protein 1 (PD-1), and presence of CD8+ tumor infiltrating lymphocytes (TILs) in MPNST, and correlate these findings with clinical behavior and outcome. Results: PD-L1 staining of at least 1% was seen in 0/20 nerves, 2/68 benign lesions and 9/53 MPNST. Two of 68 benign lesions and 7/53 (13%) MPNST had at least 5% PD-L1 staining. CD8 staining of at least 5% was seen in 1/20 (5%) nerves, 45/68 (66%) benign lesions and 30/53 (57%) MPNST. PD-L1 was statistically more prevalent in MPNST than both nerves and benign lesions (p=0.049 and p=0.008, respectively). Expression of PD-1 was absent in all tissue specimens. There was no correlation of PD-L1 or CD8 expression with disease state (primary versus metastatic) or patient survival. Methods: A comprehensive PNST tissue microarray was created from 141 surgical specimens including primary, recurrent, and metastatic MPNST (n=53), neurofibromas (n=57), schwannoma (n=11), and normal nerve (n=20). Cores were stained in triplicate for PD-L1, PD-1, and CD8, and expression compared between tumor types. These data were then examined for survival correlates in 35 patients with primary MPNST. Conclusions: MPNST is characterized by low PD-L1 and absent PD-1 expression with significant CD8+ TIL presence. MPNST immune microenvironment does not correlate with patient outcome.

// Elizabeth Shurell 1, * , Maria E. Vergara-Lluri 2, * , Yunfeng Li 3 , Joseph G. Crompton 1 , Arun Singh 4 , Nicholas Bernthal 5 , Hong Wu 3 , Fritz C. Eilber 1 , Sarah M. Dry 2 1 Division of Surgical Oncology, University of California, Los Angeles, CA 90095, USA 2 Department of Pathology and Laboratory Medicine, University of California, Los Angeles, CA 90095, USA 3 Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095, USA 4 Department of Hematology/Oncology, University of California, Los Angeles, CA 90095, USA 5 Department of Orthopaedic Surgery, University of California, Los Angeles, CA 90095, USA * Co-first author Correspondence to: Fritz C. Eilber, email: fceilber@mednet.ucla.edu Keywords: NY-ESO-1, sarcoma, MPNST, liposarcoma, immunotherapy Received: July 28, 2016 Accepted: September 09, 2016 Published: September 17, 2016 ABSTRACT Background: Immunotherapy targeting cancer-testis antigen NY-ESO-1 shows promise for tumors with poor response to chemoradiation. Malignant peripheral nerve sheath tumors (MPNSTs) and liposarcomas (LPS) are chemoresistant and have few effective treatment options. Materials Methods: Using a comprehensive tissue microarray (TMA) of both benign and malignant tumors in primary, recurrent, and metastatic samples, we examined NY-ESO-1 expression in peripheral nerve sheath tumor (PNST) and adipocytic tumors. The PNST TMA included 42 MPNSTs (spontaneous n = 26, NF1-associated n = 16), 35 neurofibromas (spontaneous n = 22, NF-1 associated n = 13), 11 schwannomas, and 18 normal nerves. The LPS TMA included 48 well-differentiated/dedifferentiated (WD/DD) LPS, 13 myxoid/round cell LPS, 3 pleomorphic LPS, 8 lipomas, 1 myelolipoma, and 3 normal adipocytic tissue samples. Stained in triplicate, NY-ESO-1 intensity and density were scored. Results: NY-ESO-1 expression was exclusive to malignant tumors. 100% of myxoid/round cell LPS demonstrated NY-ESO-1 expression, while only 6% of WD/DD LPS showed protein expression, one of which was WD LPS. Of MPNST, 4/26 (15%) spontaneous and 2/16 (12%) NF1-associated MPNSTs demonstrated NY-ESO-1 expression. Strong NY-ESO-1 expression was observed in myxoid/round cell and dedifferentiated LPS, and MPNST in primary, neoadjuvant, and metastatic settings. Conclusions: We found higher prevalence of NY-ESO-1 expression in MPNSTs than previously reported, highlighting a subset of MPNST patients who may benefit from immunotherapy. This study expands our understanding of NY-ESO-1 in WD/DD LPS and is the first demonstration of staining in a WD LPS and metastatic/recurrent myxoid/round cell LPS. These results suggest immunotherapy targeting NY-ESO-1 may benefit patients with aggressive tumors resistant to conventional therapy.

Pharmacologic inhibitors of the serine/threonine kinase Akt, initially aimed at deranged oncogenic pathways in tumors, have recently been shown to act as immunomodulators that markedly enhance the antitumor properties of T cells. Repurposing Akt inhibitors to improve antitumor immunity may be viewed as a manifestation of a larger paradigmatic shift in which hallmark characteristics of cancer (e.g., immune evasion), rather than merely causal features (e.g., somatic mutations) can be exploited for therapeutic benefit.

In the original article the middle initial of Nicholas D. Klemen was inadvertently omitted. On the first page of the original article, under the heading A Novel Way to Fight Cancer, there was an error in the third sentence. The corrected text is as follows: For example, the presence of T cells within tumors of colorectal origin can be a superior predictor of patient survival compared with the standard histopathologic methods currently used to stage colorectal cancer.6,7.

Meeting abstracts Tumor cells and tumor infiltrating lymphocytes (TIL) competes for glucose and other metabolites within the tumor microenvironment for their survival. Glucose consumption by tumors metabolically restricts T cell's ability to produce effector cytokines and therefore approaches to

The ability of tumor-reactive CD8+ T cells to eradicate tumors following adoptive transfer of autologous tumor-infiltrating lymphocytes correlates with their capacity to proliferate and persist for long periods of time. These qualities are found predominantly in naive and less differentiated memory cells including memory stem cells (TSCM) and central memory cells (TCM), but the metabolic control of differentiation remains unknown. T cell differentiation is characterized by an increase in glycolysis and a rise in mitochondrial metabolism characterized by increased mitochondrial mass, activity and reactive oxygen species generation. We previously demonstrated that inhibition of glycolysis resulted in memory T cell formation and anti-tumor function; however the specific role that mitochondrial metabolism plays in regulating T cell differentiation remains unknown. Using TMRM, a fluorescent dye that measures mitochondrial potential in T cells, we found that mitochondrial membrane potential (MP) and reactive oxygen species in T cells critically control T cell longevity. Cells with lower membrane potential (‘low MP’) had a molecular profile characteristic of stem cell memory precursors and displayed an enhanced ability to enter the memory pool as compared to cells displaying higher mitochondrial potential (‘high MP’) characteristic of short lived effectors. Global metabolomic and functional studies revealed that ‘low MP’ cells exhibited increased levels of intracellular free fatty acid metabolites, increased expression of CPT-1a, a rate limiting enzyme involved in fatty acid oxidation and increased mitochondrial spare respiratory capacity, a metabolic property characteristic of long lived memory T cells. In comparison, ‘high MP’ T cells displayed enhanced lactate production. Most importantly, we observed a 100 fold increase in the frequency of secondary memory CD8+ T cells 300 days after adoptive transfer of 'low MP' as compared to ‘high MP’ T cells. In tumor-bearing mice, ‘low MP’ cells exhibited increased cytokine functionality and resulted in the regression of large, vascularized tumors. Subsequent studies revealed that ‘high MP’ cells displayed increased DNA damage that leads to accelerated senescence, but the ‘low MP’ cells exhibit reduced ROS and DNA repair which allows them to persist longer than the ‘high MP’ cells in vivo following adoptive transfer. Our findings suggest that mitochondrial membrane potential critically controls the differentiation of memory versus effector T cells. Pharmacological interventions augmenting mitochondrial spare respiratory capacity hold great promise to improve T cell based immunotherapy for cancer.