Meghan L Good

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• Islam, S. M., Maeda, T., Tamaoki, N., Good, M. L., Kishton, R. J., Paria, B. C., Yu, Z., Bosch-Marce, M., Bedanova, N. M., Liu, C., Kruhlak, M. J., Restifo, N. P., & Vizcardo, R. (2023). Reprogramming of Tumor-reactive Tumor-infiltrating Lymphocytes to Human-induced Pluripotent Stem Cells. Cancer research communications, 3(5), 917-932.
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  Tumor-infiltrating lymphocytes (TIL) that can recognize and kill tumor cells have curative potential in subsets of patients treated with adoptive cell transfer (ACT). However, lack of TIL therapeutic efficacy in many patients may be due in large part to a paucity of tumor-reactive T cells in TIL and the exhausted and terminally differentiated status of those tumor-reactive T cells. We sought to reprogram exhausted TIL that possess T-cell receptors (TCR) specific for tumor antigens into induced pluripotent stem cells (iPSC) to rejuvenate them for more potent ACT. We first attempted to reprogram tumor neoantigen-specific TIL by αCD3 Ab prestimulation which resulted in failure of establishing tumor-reactive TIL-iPSCs, instead, T cell-derived iPSCs from bystander T cells were established. To selectively activate and enrich tumor-reactive T cells from the heterogenous TIL population, CD8 PD-1 4-1BB TIL population were isolated after coculture with autologous tumor cells, followed by direct reprogramming into iPSCs. TCR sequencing analysis of the resulting iPSC clones revealed that reprogrammed TIL-iPSCs encoded TCRs that were identical to the pre-identified tumor-reactive TCRs found in minimally cultured TIL. Moreover, reprogrammed TIL-iPSCs contained rare tumor antigen-specific TCRs, which were not detectable by TCR sequencing of the starting cell population. Thus, reprogramming of PD-1 4-1BB TIL after coculture with autologous tumor cells selectively generates tumor antigen-specific TIL-iPSCs, and is a distinctive method to enrich and identify tumor antigen-specific TCRs of low frequency from TIL.
• Tamaoki, N., Siebert, S., Maeda, T., Ha, N. H., Good, M. L., Huang, Y., Vodnala, S. K., Haro-Mora, J. J., Uchida, N., Tisdale, J. F., Sweeney, C. L., Choi, U., Brault, J., Koontz, S., Malech, H. L., Yamazaki, Y., Isonaka, R., Goldstein, D. S., Kimura, M., , Takebe, T., et al. (2023). Self-organized yolk sac-like organoids allow for scalable generation of multipotent hematopoietic progenitor cells from induced pluripotent stem cells. Cell reports methods, 3(4), 100460.
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  Although the differentiation of human induced pluripotent stem cells (hiPSCs) into various types of blood cells has been well established, approaches for clinical-scale production of multipotent hematopoietic progenitor cells (HPCs) remain challenging. We found that hiPSCs cocultured with stromal cells as spheroids (hematopoietic spheroids [Hp-spheroids]) can grow in a stirred bioreactor and develop into yolk sac-like organoids without the addition of exogenous factors. Hp-spheroid-induced organoids recapitulated a yolk sac-characteristic cellular complement and structures as well as the functional ability to generate HPCs with lympho-myeloid potential. Moreover, sequential hemato-vascular ontogenesis could also be observed during organoid formation. We demonstrated that organoid-induced HPCs can be differentiated into erythroid cells, macrophages, and T lymphocytes with current maturation protocols. Notably, the Hp-spheroid system can be performed in an autologous and xeno-free manner, thereby improving the feasibility of bulk production of hiPSC-derived HPCs in clinical, therapeutic contexts.
• Lin, A. C., Olecki, E. J., Good, M. L., Cowart, C., & Scow, J. S. (2022). Carbon Dioxide Embolism Resulting From Liver Laceration During Peritoneal Optical Trocar Entry. Cureus, 14(8), e28132.
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  Venous air emboli have been reported to occur in numerous settings, including trauma, various surgical procedures, both laparoscopic and radiologically, and even idiopathically. In this case study, a liver laceration was made during a robot-assisted left colectomy and colostomy in a 69-year-old female resulting in air embolism during insufflation. A drop in end-tidal CO was noted and the patient went into immediate cardiac arrest. Adequate pressure was applied and over-suturing of the liver laceration was made with reverse Trendelenburg positioning during the administration of cardiopulmonary resuscitation (CPR) for approximately one minute. The patient completed an open hemicolectomy the following day and made a complete recovery. Preventative and intraoperative measures to prevent further recurrences of venous air emboli are discussed.
• Malekzadeh, P., Good, M., & Hughes, M. S. (2021). Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) with cisplatin in pediatric patients with peritoneal mesothelioma: a single institution experience and long term follow up. International journal of hyperthermia : the official journal of European Society for Hyperthermic Oncology, North American Hyperthermia Group, 38(1), 326-331.
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  Malignant peritoneal mesothelioma (MPM) is a lethal cancer, with approximately 2% of diagnoses occurring in patients less than 40 years of age. The purpose of this study is to report the only long-term follow up and survival of pediatric patients with MPM after multi-modality therapy including cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC).
• McDonald, J. D., Gupta, S., Shindorf, M. L., Copeland, A., Good, M. L., Sadowski, S. M., & Nilubol, N. (2021). Pancreatic insufficiency following pancreatectomy: Does underlying tumor syndrome confer a greater risk?. American journal of surgery, 221(2), 465-471.
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  The risk of postoperative pancreatic exocrine insufficiency (PPEI) is unknown in patients with multiple endocrine neoplasia type I (MEN1) and von Hippel-Lindau (VHL) who require resection of pancreatic neuroendocrine tumors (PNETs).
• Good, M. L., Malekzadeh, P., Kriley, I. R., Shah, N. N., Kleiner, D. E., Calvo, K., Hernandez, J. M., & Davis, J. L. (2020). Intrahepatic cholangiocarcinoma as a rare secondary malignancy after allogeneic hematopoietic stem cell transplantation for childhood acute lymphoblastic leukemia: A case report. Pediatric transplantation, 24(2), e13653.
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  Secondary malignancies are a significant cause of non-relapse mortality in patients who undergo allogeneic HCT. However, secondary liver cancer is rare, and ICC following HCT has never been reported in the literature. Secondary solid cancers typically have a long latency period, and cholangiocarcinoma is classically a malignancy occurring in older individuals. Here, we report the first case of secondary ICC, which presented just 3 years after HCT in a young adult with a history of childhood ALL. A 26-year-old male with history of precursor B-cell ALL presented with asymptomatic elevated liver function tests 3 years after HCT. Laboratories were indicative of biliary obstruction. ERCP showed focal biliary stricturing of the common and left hepatic ducts. MRCP revealed left intrahepatic duct dilatation, suggestive of intrahepatic obstructing mass. Additional workup lead to a clinical diagnosis of ICC. The patient underwent left hepatectomy with extrahepatic bile duct resection and portal lymphadenectomy. Surgical pathology was consistent with moderately differentiated cholangiocarcinoma. Our case illustrates a rare SMN following HCT for ALL. It is the first case report of ICC occurring as a secondary cancer in this patient population. Although cholangiocarcinoma is characteristically diagnosed in the older population, it must remain on the differential for biliary obstruction in post-HCT patients.
• Good, M. L., Malekzadeh, P., Ruff, S. M., Gupta, S., Copeland, A., Pacak, K., Nilubol, N., Kebebew, E., & Patel, D. (2020). Surgical Resection of Pheochromocytomas and Paragangliomas is Associated with Lower Cholesterol Levels. World journal of surgery, 44(2), 552-560.
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  Catecholamine excess in patients with pheochromocytomas or paragangliomas (PPGLs) can lead to hypertension, diabetes and hyperlipidemia. The aim was to investigate the prevalence of hyperlipidemia and the effect of surgical resection.
• Lo, W., Ayabe, R. I., Kariya, C. M., Good, M. L., Steinberg, S. M., Davis, J. L., Ripley, R. T., & Hernandez, J. M. (2020). Stage and disease-free interval help select patients for surgical management of locally recurrent and metastatic adrenocortical carcinoma. Journal of surgical oncology, 121(2), 228-233.
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  Chemotherapeutic options for patients with recurrent/metastatic adrenocortical carcinoma (ACC) are limited, leading to consideration for surgical management. We sought to determine characteristics associated with an unequivocal survival benefit amongst patients undergoing re-resection or metastasectomy.
• Malekzadeh, P., Cowan, K., Steinberg, S. M., Camphausen, K. A., Shriver, C., Merino, M. J., Good, M. L., Berman, A., & Danforth, D. N. (2020). Twenty-five-Year Follow-up of a Prospective Randomized Trial Comparing Preoperative Versus Postoperative FLAC/Granulocyte Colony-Stimulating Factor Chemotherapy for Stage II Breast Cancer. American journal of clinical oncology, 43(5), 334-339.
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  Preoperative chemotherapy is important in the management of women with breast cancer, with the ability to downstage the breast primary tumor and axillary lymph nodes. Long-term studies are needed to identify late toxicities, recurrence patterns, and equivalency with postoperative chemotherapy for recurrence-free survival (RFS) and overall survival (OS).
• Malekzadeh, P., Yossef, R., Cafri, G., Paria, B. C., Lowery, F. J., Jafferji, M., Good, M. L., Sachs, A., Copeland, A. R., Kim, S. P., Kivitz, S., Parkhurst, M. R., Robbins, P. F., Ray, S., Xi, L., Raffeld, M., Yu, Z., Restifo, N. P., Somerville, R. P., , Rosenberg, S. A., et al. (2020). Antigen Experienced T Cells from Peripheral Blood Recognize p53 Neoantigens. Clinical cancer research : an official journal of the American Association for Cancer Research, 26(6), 1267-1276.
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  The purpose of this study was to evaluate antigen experienced T cells in peripheral blood lymphocytes (PBL) for responses to p53 neoantigens.
• Martin, S. P., Drake, J., Wach, M. M., Ruff, S. M., Diggs, L. P., Wan, J. Y., Good, M. L., Dominguez, D. A., Ayabe, R. I., Glazer, E. S., Dickson, P. V., Davis, J. L., Deneve, J. L., & Hernandez, J. M. (2020). Resection and chemotherapy is the optimal treatment approach for patients with clinically node positive intrahepatic cholangiocarcinoma. HPB : the official journal of the International Hepato Pancreato Biliary Association, 22(1), 129-135.
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  Clinically lymph node positive (cLNP) intrahepatic cholangiocarcinoma (ICC) carries a poor prognosis, without clear management guidelines for the practicing clinician. We sought to evaluate current practice patterns for cLNP ICC, including associations with survival.
• Good, M. L., Vizcardo, R., Maeda, T., Tamaoki, N., Malekzadeh, P., Kawamoto, H., & Restifo, N. P. (2019). Using Human Induced Pluripotent Stem Cells for the Generation of Tumor Antigen-specific T Cells. Journal of visualized experiments : JoVE.
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  The generation and expansion of functional T cells in vitro can lead to a broad range of clinical applications. One such use is for the treatment of patients with advanced cancer. Adoptive T cell transfer (ACT) of highly enriched tumor antigen-specific T cells has been shown to cause durable regression of metastatic cancer in some patients. However, during expansion, these cells may become exhausted or senescent, limiting their effector function and persistence in vivo. Induced pluripotent stem cell (iPSC) technology may overcome these obstacles by leading to in vitro generation of large numbers of less differentiated tumor antigen-specific T cells. Human iPSC (hiPSC) have the capacity to differentiate into any type of somatic cell, including lymphocytes, which retain the original T cell receptor (TCR) genomic rearrangement when a T cell is used as a starting cell. Therefore, reprogramming of human tumor antigen-specific T cells to hiPSC followed by redifferentiation to T cell lineage has the potential to produce rejuvenated tumor antigen-specific T cells. Described here is a method for generating tumor antigen-specific CD8αβ single positive (SP) T cells from hiPSC using OP9/DLL1 co-culture system. This method is a powerful tool for in vitro T cell lineage generation and will facilitate the development of in vitro derived T cells for use in regenerative medicine and cell-based therapies.
• Ruff, S. M., Ayabe, R. I., Malekzadeh, P., Good, M. L., Wach, M. M., Gonzales, M. K., Tirosh, A., Nilubol, N., Pacak, K., Kebebew, E., & Patel, D. (2019). MicroRNA-210 May Be a Preoperative Biomarker of Malignant Pheochromocytomas and Paragangliomas. The Journal of surgical research, 243, 1-7.
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  Currently, no reliable predictive clinical or laboratory tests exist that can accurately distinguish between benign and malignant pheochromocytomas or paragangliomas (PPGLs). The aim of this study was to investigate if serum microRNA-210 (miR-210) levels could be a marker of malignancy in patients with PPGLs.
• Vizcardo, R., Rafiqul Islam, S. M., Maeda, T., Tamaoki, N., Good, M. L., Klemen, N. D., Bosch-Marce, M., Jia, L., Kruhlak, M. J., & Restifo, N. P. (2019). A Three-dimensional Thymic Culture System to Generate Murine Induced Pluripotent Stem Cell-derived Tumor Antigen-specific Thymic Emigrants. Journal of visualized experiments : JoVE.
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  The inheritance of pre-rearranged T cell receptors (TCRs) and their epigenetic rejuvenation make induced pluripotent stem cell (iPSC)-derived T cells a promising source for adoptive T cell therapy (ACT). However, classical in vitro methods for producing regenerated T cells from iPSC result in either innate-like or terminally differentiated T cells, which are phenotypically and functionally distinct from naïve T cells. Recently, a novel three-dimensional (3D) thymic culture system was developed to generate a homogenous subset of CD8αβ antigen-specific T cells with a naïve T cell-like functional phenotype, including the capacity for proliferation, memory formation, and tumor suppression in vivo. This protocol avoids aberrant developmental fates, allowing for the generation of clinically relevant iPSC-derived T cells, designated as iPSC-derived thymic emigrants (iTE), while also providing a potent tool to elucidate the subsequent functions necessary for T cell maturation after thymic selection.
• Lo, W. M., Good, M. L., Nilubol, N., Perrier, N. D., & Patel, D. T. (2018). Tumor Size and Presence of Metastatic Disease at Diagnosis are Associated with Disease-Specific Survival in Parathyroid Carcinoma. Annals of surgical oncology, 25(9), 2535-2540.
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  The incidence of parathyroid carcinoma is reported to be rising. There is minimal data on prognostic variables associated with cancer-specific survival. The objectives of this study were to evaluate the trends in incidence and assess prognostic factors.
• Vizcardo, R., Klemen, N. D., Islam, S. M., Gurusamy, D., Tamaoki, N., Yamada, D., Koseki, H., Kidder, B. L., Yu, Z., Jia, L., Henning, A. N., Good, M. L., Bosch-Marce, M., Maeda, T., Liu, C., Abdullaev, Z., Pack, S., Palmer, D. C., Stroncek, D. F., , Ito, F., et al. (2018). Generation of Tumor Antigen-Specific iPSC-Derived Thymic Emigrants Using a 3D Thymic Culture System. Cell reports, 22(12), 3175-3190.
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  Induced pluripotent stem cell (iPSC)-derived T cells may provide future therapies for cancer patients, but those generated by current methods, such as the OP9/DLL1 system, have shown abnormalities that pose major barriers for clinical translation. Our data indicate that these iPSC-derived CD8 single-positive T cells are more like CD4CD8 double-positive T cells than mature naive T cells because they display phenotypic markers of developmental arrest and an innate-like phenotype after stimulation. We developed a 3D thymic culture system to avoid these aberrant developmental fates, generating a homogeneous subset of CD8αβ antigen-specific T cells, designated iPSC-derived thymic emigrants (iTEs). iTEs exhibit phenotypic and functional similarities to naive T cells both in vitro and in vivo, including the capacity for expansion, memory formation, and tumor suppression. These data illustrate the limitations of current methods and provide a tool to develop the next generation of iPSC-based antigen-specific immunotherapies.