GD2‐directed CAR‐T cells in combination with HGF‐targeted neutralizing antibody (AMG102) prevent primary tumor growth and metastasis in Ewing sarcoma. Issue 11 (6th November 2019)

• Record Type: Journal Article
• Authors: Charan, Manish; Dravid, Piyush; Cam, Maren; Audino, Anthony; Gross, Amy C.; Arnold, Michael A.; Roberts, Ryan D.; Cripe, Timothy P.; Pertsemlidis, Alexander; Houghton, Peter J.; Cam, Hakan
• Is Part Of: International journal of cancer. Volume 146:Issue 11(2020)
• Page Start: 3184
• Page End: 3195
• Publication Date: 2019-11-06
• Subjects: Ewing sarcoma -- metastasis -- delta133p53 -- HGF -- AMG102 -- CAR‐T cell therapy -- preclinical studies; Cancer -- Periodicals; Cancer -- Prevention -- Periodicals; 616.994
• DOI: 10.1002/ijc.32743
• Languages: English
• ISSNs: 0020-7136

Abstract

Abstract : Ewing sarcoma (EWS) is the second most common and aggressive type of metastatic bone tumor in adolescents and young adults. There is unmet medical need to develop and test novel pharmacological targets and novel therapies to treat EWS. Here, we found that EWS expresses high levels of a p53 isoform, delta133p53. We further determined that aberrant expression of delta133p53 induced HGF secretion resulting in tumor growth and metastasis. Thereafter, we evaluated targeting EWS tumors with HGF receptor neutralizing antibody (AMG102) in preclinical studies. Surprisingly, we found that targeting EWS tumors with HGF receptor neutralizing antibody (AMG102) in combination with GD2‐specific, CAR‐reengineered T‐cell therapy synergistically inhibited primary tumor growth and establishment of metastatic disease in preclinical models. Furthermore, our data suggested that AMG102 treatment alone might increase leukocyte infiltration including efficient CAR‐T access into tumor mass and thereby improves its antitumor activity. Together, our findings warrant the development of novel CAR‐T‐cell therapies that incorporate HGF receptor neutralizing antibody to improve therapeutic potency, not only in EWS but also in tumors with aberrant activation of the HGF/c‐MET pathway. Abstract : What's new? Ewing sarcoma (EWS) is an aggressive malignancy with poor long‐term outcomes. Therapeutic advances for EWS, however, are hindered by a lack of pharmacological targets. Here, EWS tumors were found to aberrantly express hepatocyte growth factor (HGF), with EWS tumor growth and metastasis promoted by elevated HGF secretion. High EWS secretion was driven by an oncogenic p53 isoform, delta133p53. In preclinical studies, EWS tumor‐targeting with HGF receptor‐neutralizing antibody, combined with GD2‐specific CAR‐reengineered T‐cell therapy, resulted in synergistic inhibition of primary tumor growth and establishment of metastatic disease. The findings lay the groundwork for future clinical trials in children affected by EWS.