Ricklie Ann Julian

Interests

Research

early phase clinical trial development in head and neck/thoracic malignancies; cancer prevention

Teaching

non-small cell lung cancer, small cell lung cancer, mesothelioma; head and neck cancer; cutaneous squamous cell carcinoma

Courses

No activities entered.

Scholarly Contributions

Journals/Publications

• Chung, C. H., Adkins, D. R., Colevas, A. D., Rodriguez, C. P., Park, J. C., Gibson, M. K., Sukari, A., Burtness, B., Johnson, F. M., Julian, R., Saba, N. F., Worden, F. P., Dunn, L., Seiwert, T. Y., Jotte, R. M., Haddad, R. J., Gabrail, N., Bauman, J. E., Chaney, M., , Agensky, L., et al. (2024). 674 A phase 1 dose-escalation and expansion study of CUE-101, given as monotherapy in 3L and in combination with pembrolizumab in 1L recurrent/metastatic HPV16+ head and neck cancer patients. JCO. doi:DOI:10.1200/JCO.2024.42.16
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  Background Immuno-STATs are modular T cell engagers engineered to selectively activate tumor-antigen specific CD8+ T cells via targeted delivery of cytokines. CUE-101, the first Immuno-STAT in clinical trials, is composed of a human leukocyte antigen (HLA) complex, HLA-A*0201, a peptide epitope derived from the HPV16 E7 protein, and 4 molecules of attenuated human interleukin-2 (IL-2) designed to bind, expand, and activate HPV16-specific CD8+ T cells for the treatment of HPV16+ cancers. Methods CUE-101–01 is an ongoing first-in-human study in HLA-A*0201 patients with HPV16+ recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC). Escalating doses of CUE-101 monotherapy (0.06 mg/kg to 8 mg/kg) were evaluated in R/M HNSCC refractory to ≥ 1 platinum-based or checkpoint inhibitor therapy and in combination with pembrolizumab (1 mg/kg to 4 mg/kg + 200 mg pembrolizumab) in the first line treatment of PD-L1+ R/M HNSCCs followed by expanded enrollment at the recommended phase 2 dose (RP2D). Therapy was administered every 3 weeks until disease progression or intolerable toxicity. Safety, PK/PD, and antitumor activity were assessed. Results As of June 22, 2023, 71 patients have been enrolled. Following monotherapy and combination therapy dose escalation, 4 mg/kg of CUE-101 was chosen as the RP2D for both monotherapy and pembrolizumab combination cohorts. Monotherapy RP2D enrollment is complete and combination RP2D enrollment is ongoing. Adverse events have been manageable and are consistent with the CUE-101 mechanism of action and underlying disease. Grade 3 AEs reported include lymphocyte count decreased (11.3%), anemia (7.0%), decreased appetite and infusion-related reaction (4.2%). PD data demonstrate selective expansion of HPV-16 E711–20-specific CD8+ T cells, sustained increase in NK cells with only transient increase in Treg cells. Among 19 evaluable monotherapy RP2D patients, 1 PR and 6 durable SD (SD ≥ 12 weeks) were observed, with mOS of 14 months. Among 16 evaluable RP2D CUE-101 and pembrolizumab combination patients at data cut-off, 1 uCR, 4 PRs, 2 uPR, and 4 durable SDs were observed. Of the 7 patients with objective responses, 5 achieved >99% reduction in HPV16 cfDNA, 4 by week 6, with 2 patients pending analysis at time of data cut-off. Conclusions CUE-101 demonstrates safety, tolerability and results in clinical benefit. Patients treated with CUE-101 monotherapy in 3L showed a long OS and CUE-101 and pembrolizumab combination resulted in an ORR of 44% with a corresponding decrease in HPV16 cfDNA in the 1L treatment of patients with HPV16+ R/M HNSCC. Acknowledgements The authors would like to thank all the patients who are participating in this study. The study is sponsored by Cue Biopharma, in collaboration with Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA and support from LG Chem, Ltd., Seoul, South Korea. Trial Registration Clinicaltrials.gov NCT03978689 Ethics Approval This study was approved by IRBs at all study sites: Advarra Pro00037736, IRB 52744, HRPO# 201905108, DF/HCC IRB# 19–374, WIRB STUDY00008948, IRB 191714, 2019–087, WIRB 2000026098, 2019–0578, WIRB 1908869642, WIRB IRB00112341, IRB 20–073, IRB00255391, IRBMED HUM00165746, US Oncol IRB00001113, WCG IRB00000533.
• Gainor, J. F., Patel, M. R., Weber, J. S., Gutierrez, M., Bauman, J. E., Clarke, J., Julian, R., Scott, A. J., Geiger, J., Kirtane, K., Robert-Tissot, C., Coder, B., Tasneem, M., Sun, J., Zheng, W., Gerbereux, L., Laino, A. S., Pollard, J., Hou, P., , Sehgal, V., et al. (2024). 1530 T-cell responses to individualized neoantigen therapy (INT) mRNA-4157 (V940) as monotherapy or in combination with pembrolizumab. Cancer Discovery, 2209-2223. doi:10.1158/2159-8290.CD-24-0158
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  Background The identification of cancer-specific T cell receptor (TCR) sequences is paramount to the advancement of cancer immunotherapies. Recent studies and clinical trials have shown that monoclonal T cell therapy is prone to immune evasion of cancer cells by loss of HLA heterozygosity and low antigen heterogeneity. Cocktail T cell therapy which comprises of TCRs corresponding to multiple HLAs and antigens has been proposed to improve the efficacy of adoptive cell transfer therapy. In addition to CD8+ cytotoxic T cells, neoantigen-specific CD4+ T cells, while identified as important for immunotherapy-induced anti-tumor responses, remain a largely untapped therapeutic resources due to the challenging nature of identification and isolation. Hence, a rapid and high-throughput discovery of both CD8+ and CD4+ TCRs against multiples Class I and II HLAs and cancer antigens is an urgent need. We engineered peptide-bound major histocompatibility complex (pMHC) proteins as capture agents for cancer-specific T cells. The design of these single-chain-trimers (SCTs) enables high-throughput multiplexing for identification and isolation of cancer-targeting CD4+ and CD8+ T cells from multiple patients against large panels of cancer antigens. We applied the technology to identify CD8+ and CD4+ TCRs against oncogenic proteins E6 and E7 from HPV-16, which is the leading cause of cervical cancer. Methods A panel of 200+ Class I SCTs and 100+ Class II SCTs were designed and expressed in a high-throughput platform. PBMCs from precancerous HPV-16+ patients with cervical lesions were collected and enriched with CD8+ and CD4+ T cells. A large pool of 200+ Class I SCT tetramer pool with barcode as antigen identifier was used to capture cancer-specific CD8+ T cells. A computational analysis pipeline was established to pair TCR α and β. HLA-matching cognate antigen was assigned to each TCR pair after UMI count correction and noise removal. The antigen-specific TCRs are subsequently sequenced, validated for functionality, and analyzed for therapeutic applications. Results We identified 43 CD8+ TCR pairs against E6 and E7 oncoproteins from HPV-16 and they are in progress for pre-clinical validation. Conclusions The SCT platform enables rapid identification of cancer-specific CD+ and CD4+ T cells and allows detailed characterization of anti-tumor T cells for which alternative solutions are extremely limited. We applied the technology to PBMCs extracted from HPV-16 related precancerous patients in a clinical trial and discovered cancer-specific TCRs. In summary, the application of the SCT technology is of high value to the fundamental and clinical immune-oncology studies.
• Bauman, J. E., Saba, N. F., Roe, D., Bauman, J. R., Kaczmar, J., Bhatia, A., Muzaffar, J., Julian, R., Wang, S., Bearelly, S., Baker, A., Steuer, C., Giri, A., Burtness, B., Centuori, S., Caulin, C., Klein, R., Saboda, K., Obara, S., & Chung, C. H. (2023). Randomized Phase II Trial of Ficlatuzumab With or Without Cetuximab in Pan-Refractory, Recurrent/Metastatic Head and Neck Cancer. Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 41(22), 3851-3862.
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  Primary or acquired resistance to cetuximab, an antiepidermal growth factor receptor monoclonal antibody (mAb), minimizes its utility in recurrent/metastatic head and neck squamous cell carcinoma (HNSCC). Aberrant hepatocyte growth factor/cMet pathway activation is an established resistance mechanism. Dual pathway targeting may overcome resistance.
• Chung, C. H., Colevas, D., Adkins, D., Park, J. C., Rodriguez, C. P., Gibson, M. K., Sukari, A., Burtness, B., Johnson, F. M., Julian, R., Saba, N. F., Dunn, L., Seiwert, T. Y., Worden, F. P., Haddad, R. J., Gabrail, N., Bauman, J. E., Agensky, L., Goel, A., , Lynam, R., et al. (2023). 681 A phase 1 study of CUE-101, a novel HPV16 E7-pHLA-IL2-Fc fusion protein, as monotherapy and in combination with pembrolizumab in patients with recurrent/metastatic HPV16+ head and neck cancer. JCO. doi:10.1136/jitc-2022-sitc2022.0681
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  Background Immuno-STATsTM are modular fusion proteins designed for the selective delivery of IL-2 to tumor-antigen specific CD8+ T cells. CUE-101, the first Immuno-STAT in clinical trials, is composed of a human leukocyte antigen (HLA) complex, HLA-A*0201, a peptide epitope derived from the HPV16 E7 protein, and 4 molecules of reduced affinity human interleukin-2 (IL-2) designed to bind, expand, and activate HPV16-specific CD8+ T cells for the treatment of HPV16+ cancers. Methods CUE-101-01 is a first-in-human study in patients with HLA-A*0201 genotype and HPV16+ recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC). R/M HNSCC patients refractory to ≥ 1 platinum- or checkpoint-inhibitor-based systemic therapies received CUE-101 monotherapy. Patients with previously untreated PD-L1+ (CPS ≥ 1) R/M HNSCC received CUE-101 and pembrolizumab 200 mg. Therapy was administered every 3 weeks until disease progression or unacceptable toxicity. Escalating doses of CUE-101 monotherapy or in combination with pembrolizumab were evaluated, followed by expanded enrollment at the recommended phase 2 dose (RP2D). Objectives included evaluation of safety, pharmacokinetics (PK), pharmacodynamics (PD), and antitumor activity. Results As of July 25, 2022, 62 patients have received CUE-101 ranging from 0.06 to 8 mg/kg/dose. The most common adverse events included fatigue (46%), anemia (24%), chills (24%), and hyponatremia (22%). In the monotherapy dose escalation portion, a MTD was not identified, and 4 mg/kg was chosen as the RP2D based on PK, PD, and preliminary clinical activity. CUE-101 dose escalation from 1 to 4 mg/kg in combination with pembrolizumab 200 mg has been completed with no DLTs observed and expansion of CUE-101 at 4 mg/kg with pembrolizumab is ongoing. PK data demonstrate dose-dependent increases in drug exposure that are sustained upon repeat dosing. PD data demonstrate selected expansion of HPV-16 E711-20-specific CD8+ T cells in the peripheral blood. Of the 19 evaluable patients treated with CUE-101 monotherapy at the RP2D of 4 mg/kg, 1 patient experienced partial response (PR) and 7 stable disease (SD) for ≥ 12 weeks. Of the 10 evaluable patients treated with CUE-101 plus pembrolizumab, 3 patients experienced PR (2 confirmed) and 2 patients SD for ≥ 12 weeks. Conclusions CUE-101 has a manageable safety profile and demonstrates activity alone and in combination with pembrolizumab. Acknowledgements The authors would like to thank all the patients who are participating in this study. The study is sponsored by Cue Biopharma, in collaboration with Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA and support from LG Chem, Ltd., Seoul, South Korea. Trial Registration ClinicalTrials. gov NCT03978689 Ethics Approval This study was approved by Ethics and Institutional Review Boards (IRBs) at all study sites. IRB reference numbers: Advarra Pro00037736 (Moffitt Cancer Center), IRB 52744 (Stanford University School of Medicine), HRPO# 201905108 (Washington University School of Medicine), DF/HCC IRB# 19-374 (Massachusetts General Hospital), WIRB STUDY00008948 (University of Washington, Seattle), IRB 191714 (Vanderbilt University Medical Center Vanderbilt-Ingram Cancer Center), 2019-087 Karmanos Cancer Institute, WIRB 2000026098 (Yale Cancer Center), 2019-0578 (The University of Texas MD Anderson Cancer Center), WIRB 1908869642 (University of Arizona Cancer Center), WIRB IRB00112341(Winship Cancer Institute/Emory University), IRB 20-073 (Memorial Sloan Kettering Cancer Center), IRB00255391 (Johns Hopkins University School of Medicine), IRB(IRBMED) HUM00165746 (University of Michigan Comprehensive Cancer Center), IRB0001113 (US Oncology Inc./Affiliated Oncologists, LLC), WCG IRB00000533 (Gabrail Cancer Center), IRB000001113 (George Washington University Cancer Center).
• Bauman, J. E., Julian, R., Saba, N. F., Wise-Draper, T. M., Adkins, D. R., O'Brien, P., Fidler, M. J., Gibson, M. K., Duvvuri, U., Heath-Chiozzi, M., Alvarado, D., Gedrich, R., Golden, P., & Cohen, R. B. (2022). Phase II Trial of CDX-3379 and Cetuximab in Recurrent/Metastatic, HPV-Negative, Cetuximab-Resistant Head and Neck Cancer. Cancers, 14(10).
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  In phase I development, CDX-3379, an anti-ErbB3 monoclonal antibody, showed promising molecular and antitumor activity in head and neck squamous cell carcinoma (HNSCC), alone or in combination with cetuximab. Preliminary biomarker data raised the hypothesis of enhanced response in tumors harboring mutations. This phase II, multicenter trial used a Simon 2-stage design to investigate the efficacy of CDX-3379 and cetuximab in 30 patients with recurrent/metastatic, HPV-negative, cetuximab-resistant HNSCC. The primary endpoint was objective response rate (ORR). Secondary endpoints included ORR in patients with somatic mutations, progression-free survival (PFS), overall survival (OS), and safety. Thirty patients were enrolled from March 2018 to September 2020. The ORR in genomically unselected patients was 2/30 (6.7%; 95% confidence interval [CI], 0.8-22.1). Median PFS and OS were 2.2 (95% CI: 1.3-3.6) and 6.6 months (95% CI: 2.7-7.5), respectively. Tissue was available in 27 patients including one of two responders. ORR was 1/10 (complete response; 10%; 95% CI 0.30-44.5) in the -mutated versus 0/17 (0%; 95% CI: 0-19.5) in the -wildtype cohorts. Sixteen patients (53%) experienced treatment-related adverse events (AEs) ≥ grade 3. The most common AEs were diarrhea (83%) and acneiform dermatitis (53%). Dose modification was required in 21 patients (70%). The modest ORR coupled with excessive, dose-limiting toxicity of this combination precludes further clinical development. Dual ErbB3-EGFR inhibition remains of scientific interest in HPV-negative HNSCC. Should more tolerable combinations be identified, development in an earlier line of therapy and prospective evaluation of the hypothesis warrant consideration.
• Groysman, M., Yi, S. K., Robbins, J. R., Hsu, C. C., Julian, R., Bauman, J. E., Baker, A., Wang, S. J., & Bearelly, S. (2022). The impact of socioeconomic and geographic factors on access to transoral robotic/endoscopic surgery for early stage oropharyngeal malignancy. American journal of otolaryngology, 43(1), 103243.
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  To evaluate the role of social and geographic factors on the likelihood of receiving transoral robotic surgery (TORS) or non-robotic transoral endoscopic surgery treatment in early stage oropharyngeal squamous cell carcinoma (OPSCC).
• Julian, R., Savani, M., & Bauman, J. E. (2021). Immunotherapy Approaches in HPV-Associated Head and Neck Cancer. Cancers, 13(23).
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  Immunotherapy approaches for head and neck squamous cell carcinoma (HNSCC) are rapidly advancing. Human papillomavirus (HPV) has been identified as a causative agent in a subset of oropharyngeal cancers (OPC). HPV-positive OPC comprises a distinct clinical and pathologic disease entity and has a unique immunophenotype. Immunotherapy with anti-PD1 checkpoint inhibitors has exhibited improved outcomes for patients with advanced HNSCC, irrespective of HPV status. To date, the clinical management of HPV-positive HNSCC and HPV-negative HNSCC has been identical, despite differences in the tumor antigens, immune microenvironment, and immune signatures of these two biologically distinct tumor types. Numerous clinical trials are underway to further refine the application of immunotherapy and develop new immunotherapy approaches. The aim of this review is to highlight the developing role of immunotherapy in HPV-positive HNSCC along with the clinical evidence and preclinical scientific rationale behind emerging therapeutic approaches, with emphasis on promising HPV-specific immune activators that exploit the universal presence of foreign, non-self tumor antigens.
• Bauman, J. E., Burris, H. A., Clarke, J., Patel, M. R., Cho, D., Gutierrez, M., Julian, R., Scott, A. J., Cohen, P. S., Frederick, J. P., Robert-Tissot, C., Zhou, H., Mody, K., Keating, K., Meehan, R., & Gainor, J. F. (2020). 798 Safety, tolerability, and immunogenicity of mRNA-4157 in combination with pembrolizumab in subjects with unresectable solid tumors (KEYNOTE-603): an update. Cancer Research, 84. doi:10.1136/jitc-2020-sitc2020.0798
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  Background T-cell targeting of mutation-derived epitopes (neoantigens) has shown to drive anti-tumor responses. Immunizing patients against such neoantigens in combination with a checkpoint inhibitor (CPI) may elicit greater anti-tumor responses than CPI alone. Mutations are rarely shared between patients, thus requiring a personalized approach to vaccine design. mRNA-4157 is a lipid encapsulated mRNA based personalized cancer vaccine encoding neoantigens selected using a proprietary algorithm to induce neoantigen specific T cells and associated anti-tumor responses. This report includes updates from the mRNA-4157 Phase1(P1) study. The initial data was presented at ASCO2019.1 Methods This study evaluates the safety and efficacy of mRNA-4157 as monotherapy in patients with resected solid tumors (Part A) and in combination with pembrolizumab in patients with advanced/metastatic solid tumors (Parts B). The selected solid tumors in Part A-B includes melanoma, bladder carcinoma, HPV-negative (HPV-neg) HNSCC, NSCLC, SCLC, MSI-High (MSI-h), or TMB-High cancers. Expansion cohorts includes patients with CPI-naïve MSS-CRC and HPV-neg HNSCC (Part C) and with resected melanoma (Part D). Patients receive up to 9 cycles (Q3W) of mRNA-4157 by intramuscular injection at up to 1 mg alone (Part A) or in combination with pembrolizumab (200 mg IV Q3W, Parts B-D). Pembrolizumab is administered for two cycles before the first dose of mRNA-4157 and may continue after 9 cycles of combination. Endpoints include safety, tolerability, efficacy and biomarker assessments. Results 79 patients received mRNA-4157; 16 as monotherapy and 63 in combination with pembrolizumab. Only low grade and reversible treatment related AEs were reported. 14/16 Part A patients (3 melanoma, 11 NSCLC, 2 MSI-h CRC) remained disease free on study. 28 patients in Parts B (6 bladder, 2 HNSCC, 3 melanoma, 10 NSCLC, 2 SCLC, 4 MSI-h tumor, 1 TMB-h tumor), 27 patients in Part C (10 HNSCC and 17 MSS-CRC), and 8 patients with resected melanoma (Part D) received combination. 3 CR (1 HNSCC, 1 MSI-h CRC and 1 MSI-h prostate), and 8 PR (1 bladder, 4 HNSCC, 2 SCLC and 1 MSI-h endometrial) were observed with combination. Of 10 CPI-naïve HPV-neg HNSCC patients, the response rate was 50% (1CR, 4PR, 4SD) mPFS 9.8months, which compared favorably to published rates of ~14.6% mPFS 2.0months for pembrolizumab monotherapy.2 3 Biomarker assessments including immune gene expression profiling will be presented. Conclusions mRNA-4157 has an acceptable safety profile along with observed clinical responses in combination with pembrolizumab. Preliminary efficacy analysis from CPI-naïve relapsed/refractory HPV-neg HNSCC cohort suggests activity of this combination. Study is ongoing. Trial Registration NCT03313778 Ethics Approval The study was approved by each participating sites’ local IRB. References Burris H, et al. A phase I multicenter study to assess the safety, tolerability, and immunogenicity of mRNA-4157 alone in patients with resected solid tumors and in combination with pembrolizumab in patients with unresectable solid tumors. Journal of Clinical Oncology20 May 2019;37(15):2523-2523. Seiwert T, et al. Safety and clinical activity of pembrolizumab for treatment of recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-012): an open-label, multicentre, phase 1b trial. Lancet Oncol 2016;17:956–65. Cohen E, et al. Pembrolizumab versus methotrexate, docetaxel, or cetuximab for recurrent or metastatic head-and-neck squamous cell carcinoma (KEYNOTE-040): a randomised, open-label, phase 3 study. Lancet 2019;393:10167:156-16.
• Chung, C. H., Caulin, C., Baker, A., Bearelly, S., Wang, S., Julian, R. A., Saba, N. F., Roe, D., Bauman, J. E., Bauman, J. R., Kaczmar, J. M., Burtness, B., Muzaffar, J., Steuer, C. E., Bhatia, A. K., Giri, A., Stabile, L. P., & Centuori, S. (2020). Randomized, phase II study of ficlatuzumab with or without cetuximab in patients with pan-refractory, recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC).. Journal of Clinical Oncology, 38(15_suppl), TPS6594-TPS6594. doi:10.1200/jco.2020.38.15_suppl.tps6594
• Zimmerman, S., Das, A., Wang, S., Julian, R., Gandhi, L., & Wolf, J. (2019). 2017-2018 Scientific Advances in Thoracic Oncology: Small Cell Lung Cancer. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer, 14(5), 768-783.
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  SCLC remains an aggressive, deadly cancer with only modest effect on survival from standard chemotherapy. However, with the advent of immunotherapy and comprehensive genomic and transcriptomic profiling, multiple new targets are showing promise in the clinical arena, and just recently programmed death ligand 1 inhibition has been shown to improve the efficacy of standard chemotherapy in extended-disease SCLC. Our increasing understanding of the interactions between different pathways will enable more tailored immunotherapy and targeted therapies based on specific biomarkers and rational combinations. Here we discuss the preclinical and clinical strides in 2017 and 2018 that put us on the threshold of a new era in therapeutics and will, it is hoped, translate into significant improvements in survival.
• Sabari, J. K., Julian, R. A., Ni, A., Halpenny, D., Hellmann, M. D., Drilon, A. E., Li, B. T., Poirier, J. T., Rudin, C. M., & Rekhtman, N. (2018). Outcomes of advanced pulmonary large cell neuroendocrine carcinoma stratified by RB1 loss, SLFN11 expression, and tumor mutational burden.. Journal of Clinical Oncology, 36(15_suppl), e20568-e20568. doi:10.1200/jco.2018.36.15_suppl.e20568
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  e20568Background: LCNEC is a biologically heterogeneous disease comprised of distinct subgroups characterized by genomic signatures of either SCLC or NSCLC (e.g. RB1 loss or retained). We assessed ...
• Chretien, K. C., Swenson, R., Yoon, B., Julian, R., Keenan, J., Croffoot, J., & Kheirbek, R. (2015). Tell Me Your Story: A Pilot Narrative Medicine Curriculum During the Medicine Clerkship. Journal of general internal medicine, 30(7), 1025-8.
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  Narrative medicine educational interventions may enhance patient-centered care, yet most educational interventions do not involve actual patient-provider interactions, nor do they assess narrative competence, a key skill for its practice. An experiential narrative medicine curriculum for medical students was developed and piloted.

Poster Presentations

• Bauman, J., Saba, N., Roe, D., Bauman, J., Kaczmar, J., Bhatia, A., Muzaffar, J., Julian, R., Wang, S., Bearelly, S., Baker, A., Steuer, C., Giri, A., Burtness, B., Centuori, S. M., Caulin, C., Saboda, K., Obara, S., & Chung, C. (2021, May/Spring). Randomized, phase II study of ficlatuzumab with or without cetuximab in pan-refractory, advanced head and neck squamous cell carcinoma (HNSCC).
  . ASCO.