Enhanced NK cell Immunotherapy for Treatment of Chemotherapy Refractory Sarcoma

Enhanced NK cell Immunotherapy for Treatment of Chemotherapy Refractory Sarcoma

Radiation therapy is a crucial treatment modality required to control soft tissue and advanced bone sarcomas. Despite technological advancements used to treat radioresistant sarcomas, local recurrence and metastasis continue to pose clinical challenges. Ionizing radiation can elicit anti-tumor responses by releasing tumor-specific antigens that are then visible to the immune system to promote potent T-lymphocyte priming, characterized as in situ vaccination. Radiation alone is rarely able to induce durable systemic antitumor immune responses. New immunotherapy drugs using antibody fragments such as bispecific antibodies and checkpoint inhibitors actively enhance the immune system to help fight cancer are approved for use in…  Read More »

MCL-1 inhibition unmasks BCL-2 addiction in synovial sarcoma

Metastatic Synovial Sarcoma (mSS) is frequently diagnosed in teenagers and young adults and continues to be treated with polychemotherapy with variable success. The SS18-SSX gene fusion is pathogenomic for the disease, and high expression of the anti-apoptotic BCL-2 pathologically supports the diagnosis. As the oncogenic SS18-SSX fusion gene itself is not druggable, BCL-2 inhibitor-based therapies are an appealing therapeutic opportunity. Venetoclax, an FDA-approved BCL-2 inhibitor that is revolutionizing care in some BCL-2 expressing hematological cancers, is an obvious therapeutic solution to mSS. In addition there are now dozens of venetoclax-based combination therapies in clinical trials in hematological cancers attributing to…  Read More »

Identification of novel drug targets and predictors of clinical outcomes in desmoplastic small round cell tumors using next-generation sequencing

Desmoplastic small round cell tumor (DSRCT) is a rare, highly-aggressive soft-tissue sarcoma with an overall five-year survival rate of less than 30%. Next generation sequencing (NGS) has given cancer researchers unprecedented access to the cancer genome, revealing targetable mutations, predictors of treatment response, and deepening our understanding of the genetic underpinnings of tumor development and progression. However, no large-scale genomic analysis of DSRCT has ever been performed, likely partially due to the difficulty in obtaining large numbers of primary tumor samples and partially due to lack of funding for such a rare disease. Because Memorial Sloan Kettering Cancer Center (MSK)…  Read More »

Unraveling the tumor immune microenvironment of angiosarcomas

Is immune checkpoint inhibition the solution for angiosarcoma patients? Genetic and immune profiles of angiosarcoma subtypes will lead to novel insights for the design of individualized immune checkpoint-based therapy for AS patients. Angiosarcomas are rare and aggressive tumors that arise from the vascular endothelium. Despite all therapeutic efforts, the prognosis for angiosarcoma patients is very poor with a 5-year survival of only 30-40%, urging the need for novel therapeutic approaches for these patients. Angiosarcomas can present anywhere in the body and can either develop spontaneously (primary angiosarcomas) or due to previous radiotherapy, chronic lymphedema, or exposure to UV radiation (secondary…  Read More »

Identifying mechanisms of osteosarcoma chemoresistance that arise from the lung metastatic niche

A therapy preventing the emergence of lung metastasis in adolescents with osteosarcoma could save more than 70% of the lives currently lost to this disease. This would represent the most significant improvement in outcome for osteosarcoma since the advent of chemotherapy in the 1960s. The primary cause for treatment failure in metastatic osteosarcoma is the emergence of resistance. Metastatic recurrence commonly follows a pattern of initial response to treatment followed by late development of metastatic lesions, often years after completion of therapy. Metastatic recurrences are inherently resistant to chemotherapy. Our lab has determined that tumor-derived IL6 and CXCL8 are critical…  Read More »

EWS-FLI1 triggered opportunistic de novo enhancer assembly activates potential cellular therapy targets in Ewing Sarcoma

Ewings sarcoma is a rare type of cancerous tumor that grows in bones or the soft tissue around the bones, such as cartilage or the nerves. It usually affects children and young adults between the ages of 10 to 19. Ewings sarcoma affects about 250 children and young adults every year in the United States and shows up slightly more often in males. The incidence of Ewing sarcoma has remained unchanged for 30 years. The incidence for all ages is one case per 1 million people in the United States. In patients aged 10 to 19 years, the incidence is…  Read More »

Evaluating the Chromatin Accessibility Landscape as a Driver of Clinical Behavior in Primary Treatment Naive Liposarcoma

Liposarcomas are the most common histologies of soft tissue sarcomas. Although the most common subtypes of liposarcoma, well-differentiated liposarcoma (WDLPS) and dedifferentiated liposarcoma (DDLPS), often coexist, their clinical behavior and prognosis differ dramatically. Efficacious and well tolerated systemic treatment options for both subtypes are lacking with few advances made over preceding decades. Development of novel therapies is, in part, constrained by our limited understanding of liposarcoma pathogenesis. Whole exome sequencing has shown that mutation rates are modest in coding regions of WDLPS and DDLPS genomes, with few recurrently mutated genes across series and no significant differences between histologies to explain…  Read More »

Unwinding new therapeutic opportunities in rhabdomyosarcoma: the role of RNA helicase DDX5

Rhabdomyosarcoma (RMS) is the most common soft-tissue sarcoma of childhood characterized by the inability to exit the proliferative myoblast-like stage. RMS can be divided in two main histopathological subtypes: alveolar (ARMS), mainly characterized by chromosomal translocations resulting in the oncogenic fusion transcription factors (PAX3- or PAX7-FOXO1); and embryonal (ERMS) characterized by a more heterogeneous genomic profile associated with activation of various tumor-promoting signaling pathways and/or loss of tumor surveillance. Alveolar RMS is the most aggressive subtype, associated with frequent metastasis at the time of diagnosis and limited response to treatment, resulting in poor survival rates, emphasizing the need to develop…  Read More »

Boosting Tumor Immunogenicity to Enhance Response to Immune Checkpoint Inhibitors in Soft Tissue Sarcomas

Most soft tissue sarcomas (STS) remain incurable in the metastatic setting with traditional chemotherapy. Immune checkpoint inhibitors (ICIs), including antibodies to PD-1/PD-L1 and CTLA-4, act by reversing tumor-mediated suppression of T cells. While these drugs have dramatically improved outcomes in many solid tumors, ICIs are effective in less than 20% of STS patients. Recent studies have shown that sarcoma patients who do not achieve benefit with ICIs have few T cells infiltrating the tumor tissue, and low expression of immune-related genes. One potential explanation is that due to the low mutational burden in many STS, antigen-presenting cells do not recognize…  Read More »

Imaging response to CD47 mAb immunotherapy in pediatric patients with osteosarcoma

Children with metastatic bone cancer have a poor prognosis, with an overall survival rate of less than 30%. Stanford investigators developed a new drug, monoclonal antibodies against the cancer cell marker CD47 (CD mAb), which activates specific immune cells (macrophages) in osteosarcomas to attack and eliminate cancer cells. Preclinical efficacy studies of CD47 mAb in animal models have been finalized and a phase I clinical trial will be initiated at Stanford in 2020. Since osteosarcomas will not decrease in size in response to CD47 mAb therapy, at least not in the immediate post-treatment phase, we need to develop new imaging…  Read More »