Maxwell Lee

All Publications

• Single-cell spatial transcriptomics uncovers niches that govern response to PD-1/PD-L1 blockade in cutaneous squamous cell carcinoma. Journal for immunotherapy of cancer Lee, M. Y., Sherman, A. R., Martinez Ramirez, L., Rahman, M., Zdravkovic, S., Shin, J. H., Stepanek, I., Colevas, A. D., Sunwoo, J. B., Divi, V. 2026; 14 (1)

  Abstract

  Neoadjuvant PD-1/PD-L1 blockade yields robust efficacy in advanced cutaneous squamous cell carcinoma (cSCC), yet many patients fail to achieve a complete or major pathologic response. The reasons why some patients experience response but others do not are unclear.We profiled cSCC specimens before, after 1 dose, and after 3-4 doses of PD-1/PD-L1 blockade to uncover resistance mechanisms and predict therapeutic response. In total, 27 patients across three cohorts, including two phase II trials, were studied. We created 1.7 mm tissue-core microarrays and performed single-cell spatial transcriptomics, including spatial clustering, gene-set enrichment, and spatial correlation analyses.After profiling all samples, six distinct spatial niches emerged, each differentially enriched in responders versus non-responders. A high antigen presentation niche, B/plasma cell enriched niche, and inflammatory keratinocyte niche were more frequent in responders, whereas proliferative keratinocyte, low antigen presentation myeloid, and fibroblast-rich epithelial-mesenchymal transition niches prevailed in non-responders. Notably, spatial niche profiling on pretreatment samples outperformed PD-L1 status in predicting pathologic response. Each niche displayed unique gene coexpression modules, suggesting niche-specific resistance mechanisms. Individual tumor analyses revealed varied immune evasion strategies, including defective interferon-induced antigen presentation, immunosuppressive myeloid environments, and epithelial-mesenchymal transition.Our single-cell spatial transcriptomic approach identifies six spatial niches that predict immunotherapy response better than PD-L1 status using only 1.7 mm tissue cores and may inform the development of biomarkers. Our results further underscore the heterogeneity of resistance mechanisms among cSCC patients, highlighting the need for tailored therapeutic strategies.

  View details for DOI 10.1136/jitc-2025-014067

  View details for PubMedID 41617396

• Preclinical study of a novel therapeutic vaccine for recurrent respiratory papillomatosis. NPJ vaccines Lee, M. Y., Metenou, S., Brough, D. E., Sabzevari, H., Bai, K., Jochems, C., Schlom, J., Allen, C. T. 2021; 6 (1): 86

  Abstract

  Activation of antigen-specific T-lymphocyte responses may be needed to cure disorders caused by chronic infection with low-risk human papillomavirus (lrHPV). Safe and effective adjuvant therapies for such disorders are needed. The safety and efficacy of a novel gorilla adenovirus vaccine expressing a protein designed to elicit immune responses directed against HPV6 and HPV11, PRGN-2012, was studied using in vitro stimulation of T lymphocytes from patients with recurrent respiratory papillomatosis, in vivo vaccination studies, and therapeutic studies in mice bearing tumors expressing lrHPV antigen. PRGN-2012 treatment induces lrHPV antigen-specific responses in patient T lymphocytes. Vaccination of wild-type mice induces E6-specific T-lymphocyte responses without toxicity. In vivo therapeutic vaccination of mice bearing established HPV6 E6 expressing tumors results in HPV6 E6-specific CD8+ T-lymphocyte immunity of sufficient magnitude to induce tumor growth delay. The clinical study of PRGN-2012 in patients with disorders caused by chronic infection with lrHPV is warranted.

  View details for DOI 10.1038/s41541-021-00348-x

  View details for PubMedID 34145272

  View details for PubMedCentralID PMC8213691

• Chimeric antigen receptor engineered NK cellular immunotherapy overcomes the selection of T-cell escape variant cancer cells. Journal for immunotherapy of cancer Lee, M. Y., Robbins, Y., Sievers, C., Friedman, J., Abdul Sater, H., Clavijo, P. E., Judd, N., Tsong, E., Silvin, C., Soon-Shiong, P., Padget, M. R., Schlom, J., Hodge, J., Hinrichs, C., Allen, C. 2021; 9 (3)

  Abstract

  As heterogeneous tumors develop in the face of intact immunity, tumor cells harboring genomic or expression defects that favor evasion from T-cell detection or elimination are selected. For patients with such tumors, T cell-based immunotherapy alone infrequently results in durable tumor control.Here, we developed experimental models to study mechanisms of T-cell escape and demonstrated that resistance to T-cell killing can be overcome by the addition of natural killer (NK) cells engineered to express a chimeric antigen receptor (CAR) targeting programmed death ligand-1 (PD-L1).In engineered models of tumor heterogeneity, PD-L1 CAR-engineered NK cells (PD-L1 t-haNKs) prevented the clonal selection of T cell-resistant tumor cells observed with T-cell treatment alone in multiple models. Treatment of heterogenous cancer cell populations with T cells resulted in interferon gamma (IFN-γ) release and subsequent upregulation of PD-L1 on tumor cells that escaped T-cell killing through defects in antigen processing and presentation, priming escape cell populations for PD-L1 dependent killing by PD-L1 t-haNKs in vitro and in vivo.These results describe the underlying mechanisms governing synergistic antitumor activity between T cell-based immunotherapy that results in IFN-γ production, upregulation of PD-L1 on T-cell escape cells, and the use of PD-L1 CAR-engineered NK cells to target and eliminate resistant tumor cell populations.

  View details for DOI 10.1136/jitc-2020-002128

  View details for PubMedID 33741731

  View details for PubMedCentralID PMC7986659

• Mechanisms of resistance to T cell-based immunotherapy in head and neck cancer. Head & neck Lee, M. Y., Allen, C. T. 2020; 42 (9): 2722-2733

  Abstract

  Most current approved or investigational immunotherapeutic approaches for head and neck squamous cell carcinoma are aimed at activating T cells. The majority of patients receiving such immunotherapy do not demonstrate durable tumor remission.Original articles covering tumor heterogeneity, immunoediting, immune escape, and local tumor immunosuppression were reviewed.In the face of immune pressure, subclones susceptible to T cell killing are eliminated, leaving behind resistant tumor clones in a process known as immunoediting. Such subclones of tumor cells that are resistant to T cell killing may remain sensitive to natural killer (NK) cell detection and elimination, suggesting that patients harboring such tumors may benefit from combination of T and NK cell-based immunotherapy. Even in the setting of optimal immunotherapy, the immunosuppressive tumor microenvironment may arrogate effector immune responses through a number of distinct mechanisms.Highly effective immunotherapy will likely require multimodality approaches targeting independent mechanisms of immune activation.

  View details for DOI 10.1002/hed.26158

  View details for PubMedID 32275098

• Effects of diagnostic delays in head and neck cancer patients presenting to the emergency department. Oral oncology Lee, M. Y., Huynh, J. D., Kim, D. D., Sunwoo, J. B., Chen, M. M. 2025; 168: 107467

  Abstract

  Delayed diagnosis of head and neck cancer leads to poorer survival, and whether initial presentation to the Emergency Department (ED) expedites or delays diagnosis is unclear. We retrospectively studied patients aged 65 or older, diagnosed with head and neck cancer between 2011 and 2015 using SEER Medicare data, comparing those who received first imaging in the ED with those who received it as outpatients. Both overall and disease-specific survival were assessed using Cox Proportional Hazards analysis, and bootstrapping was performed to determine an ideal interval between imaging and biopsy. Of 2282 included patients, 211 received initial imaging in the ED and were propensity score matched to 633 outpatients. ED patients had longer intervals between imaging and biopsy (44.6 % vs 11.7 % with an interval > 34 days, p < 0.001) and poorer two-year overall (47.8 % vs 60.3 %, p < 0.01) and cancer-specific (56.2 % vs 67.3 %, p < 0.01) survival compared to outpatients. Those biopsied within 34 days of imaging had statistically similar survival compared to those biopsied prior to imaging (HR = 1.13, 95 % CI 0.90-1.43), and those biopsied 34 or more days after imaging demonstrated worse survival (HR = 1.32, 95 % CI 1.01-1.72). These findings suggest that patients presenting to the ED for initial imaging may experience delays in biopsy leading to inferior survival, underscoring the importance of ensuring timely tissue diagnosis.

  View details for DOI 10.1016/j.oraloncology.2025.107467

  View details for PubMedID 40669441

• Newborn hearing screening methodology impacts the timing of diagnosis for auditory neuropathy spectrum disorder. American journal of otolaryngology Bennett, C., Yoon, P., Lee, M. Y., Wolfe, M., Anne, S., Carvalho, D. S. 2023; 44 (4): 103920

  Abstract

  Auditory Neuropathy Spectrum Disorder (ANSD) accounts for 10 % to 15 % of pediatric hearing loss. In most cases, otoacoustic emissions (OAE) are present as the outer hair cell function is normal, and the auditory brainstem response (ABR) is abnormal. Newborn hearing screen (NBHS) is completed using OAE or ABR depending on the institution. Because OAEs are often present in ANSD, NBHS done solely with OAE can miss and delay diagnosis of patients with ANSD.To assess whether NBHS methodology impacts the age of diagnosis of ANSD.This is a retrospective study of patients, 0-18 years of age, diagnosed with ANSD at two tertiary pediatric hospitals from 1/01/2010 to 12/31/2018 after referral from NBHS performed in the community. Data recorded included patient demographics, method of NBHS, NICU stay, and age at ANSD diagnosis.264 patients were diagnosed with ANSD. Of those, 123 (46.6 %) were female, and 141 (53.4 %) were male. Ninety-seven (36.8 %) were admitted to NICU and the mean stay was 6.98 weeks (STD = 10.7; CI = 4.8-9.1). The majority (244, 92.4 %) of patients had NBHS with ABR, and 20 (7.5 %) had NBHS with OAE. Patients screened with ABR were diagnosed with ANSD earlier than those who screened with OAE, with a mean age of 14.1 versus 27.3 weeks (p = 0.0397, CI = 15.2-39.3). Among those screened with ABR, median age at diagnosis was 4 months for NICU infants and 2.5 months for infants with no history of NICU stay over 5 days. In comparison, median diagnosis age was 8 months for non-NICU infants screened with OAEs.Patients with ANSD who had NBHS with ABR were diagnosed earlier than those with OAE. Our data suggest that universal screening with ABR may facilitate earlier diagnosis of ANSD and earlier evaluation for aural rehabilitation, especially in high-risk cohorts such as NICU patients. Further research is needed into factors that contribute to earlier diagnosis among patients screened with ABR.

  View details for DOI 10.1016/j.amjoto.2023.103920

  View details for PubMedID 37207575

• Primary Total Laryngectomy versus Organ Preservation for Locally Advanced T3/T4a Laryngeal Cancer. The Laryngoscope Lee, M. Y., Belfiglio, M., Zeng, J., Fleming, C. W., Koyfman, S., Joshi, N. P., Lamarre, E., Prendes, B., Scharpf, J., Lorenz, R. R., Woody, N. M., Adelstein, D. J., Geiger, J. L., Chute, D. J., Ku, J. A. 2023; 133 (5): 1122-1131

  Abstract

  Organ preservation (OP) treatment for advanced laryngeal cancer has increased compared to primary total laryngectomy. Our study compares oncologic and functional outcomes between these approaches.Retrospective cohort study.Single tertiary care institution.Retrospective review of patients receiving primary total laryngectomy or OP for laryngeal cancer between 1/1/2000 and 12/31/2018.A total of 118 patients received primary total laryngectomy and 119 received OP. Overall survival was similar between total laryngectomy and OP. When stratified by T stage, disease-free survival was worse among T3 patients receiving OP versus total laryngectomy. In T3 patients, 28 OP patients experienced local recurrence (28.9%) compared to 3 total laryngectomy patients (7.1%; p < 0.01). In total, 20 OP patients with local recurrence received salvage surgery. These patients had similar overall survival to patients who underwent initial total laryngectomy (TL). About 14 OP patients with local recurrence did not receive salvage surgery. About 89 (75.4%) TL patients achieved normal diet as compared to 64 (53.8%) OP patients (p < 0.001). In TL patients, 106 (89.8%) received primary or secondary tracheoesophageal-prosthesis, 82 (77.4%) of whom achieved completely understandable speech.There was no difference in survival by treatment in T4 patients, possibly because of strict patient selection. However, disease-free survival was worse in T3 patients receiving OP, likely due to a high local recurrence rate. Approximately 40% of patients with local recurrence were not eligible for salvage laryngectomy. TL patients had comparable swallowing and speech outcomes with OP patients.3 Laryngoscope, 133:1122-1131, 2023.

  View details for DOI 10.1002/lary.30254

  View details for PubMedID 35754153

• Immunotherapy for HPV Malignancies. Seminars in radiation oncology Lee, M. Y., Allen, C. T. 2021; 31 (4): 361-370

  Abstract

  Owing to the presence of known tumor-specific viral antigens, human papillomavirus (HPV)-associated cancers are well suited for treatment with immunotherapy designed to unleash, amplify or replace the T cell arm of the adaptive immune system. Immune checkpoint blockade designed to unleash existing T cell immunity is currently Food and Drug Administration approved for certain HPV-associated cancers. More specific immunotherapies such as therapeutic vaccines and T cell receptor-engineered cellular therapy are currently in clinical development. Such therapies may offer more specific immune activation against viral tumor antigens and decrease the risk of immune-related adverse events. Current and planned clinical study of these treatments will determine their utility in the treatment of patients with newly diagnosed advanced stage or relapsed HPV-associated cancer.

  View details for DOI 10.1016/j.semradonc.2021.02.008

  View details for PubMedID 34455991

  View details for PubMedCentralID PMC8409092

• Antigen processing and presentation in cancer immunotherapy. Journal for immunotherapy of cancer Lee, M. Y., Jeon, J. W., Sievers, C., Allen, C. T. 2020; 8 (2)

  Abstract

  Knowledge about and identification of T cell tumor antigens may inform the development of T cell receptor-engineered adoptive cell transfer or personalized cancer vaccine immunotherapy. Here, we review antigen processing and presentation and discuss limitations in tumor antigen prediction approaches.Original articles covering antigen processing and presentation, epitope discovery, and in silico T cell epitope prediction were reviewed.Natural processing and presentation of antigens is a complex process that involves proteasomal proteolysis of parental proteins, transportation of digested peptides into the endoplasmic reticulum, loading of peptides onto major histocompatibility complex (MHC) class I molecules, and shuttling of peptide:MHC complexes to the cell surface. A number of T cell tumor antigens have been experimentally validated in patients with cancer. Assessment of predicted MHC class I binding and total score for these validated T cell antigens demonstrated a wide range of values, with nearly one-third of validated antigens carrying an IC50 of greater than 500 nM.Antigen processing and presentation is a complex, multistep process. In silico epitope prediction techniques can be a useful tool, but comprehensive experimental testing and validation on a patient-by-patient basis may be required to reliably identify T cell tumor antigens.

  View details for DOI 10.1136/jitc-2020-001111

  View details for PubMedID 32859742

  View details for PubMedCentralID PMC7454179