Dronca, Roxana

Abstract Cytotoxic T lymphocytes (CTL) are indispensable in anti-tumor immunity. Although CTLs are prone to exhaustion in patients with advanced cancer, T cell resiliency explains the presence of tumor-reactive CTLs that are less exhausted, capable of cytolytic function, expansion, and rebound in response to immunotherapy to reject metastatic malignancies. However, the features of resilient T cells have not been clearly defined. In this report, we demonstrate that peripheral CX3CR1+ CD8+ T cells with low mitochondrial membrane potential rebounded CTL function quickly after radiation therapy in patients with large tumor burden portraying their functional resiliency. Furthermore, CX3CR1+ CD8+ T cell with low, but not high, mitochondrial membrane potential are highly cytotoxic, accumulate less reactive oxygen species (ROS), and express more Malic enzyme 1 (ME1). ME1 overexpression increases ATP production in a glycolysis-independent manner while concurrently curtailing excessive ROS in activated CD8+ T cells; and expands CX3CR1+NKG7+ effector CD8+ T cells with enhanced cytotoxicity. Importantly, transfection of ME1 mRNA promotes tumoricidal activity in CD8+ T cells from patients with advanced cancers. Our study reveals a mechanism used by CTLs to balance excessive ROS via ME1 to maintain a metabolic and functional resiliency. Modification of ME1 expression in CTLs may be a novel method to improve the efficacy of cancer immunotherapy by preventing T cell exhaustion. Supported by grants from Mayo Clinic Foundation and NIH (R01CA 256927-2)

PURPOSE In response to the COVID-19 pandemic, many cancer practices rapidly adopted telehealth services. However, there is a paucity of data regarding ongoing telehealth visit utilization beyond this initial response. The purpose of this study was to assess changes in variables associated with telehealth visit utilization over time. METHODS This is a cross-sectional, year-over-year, retrospective analysis of telehealth visits conducted across a multisite, multiregional cancer practice in the United States. Multivariable models examined the association of patient- and provider-level variables with telehealth utilization across outpatient visits conducted over three 8-week periods from July to August in 2019 (n = 32,537), 2020 (n = 33,399), and 2021 (n = 35,820). RESULTS The rate of telehealth utilization increased from <0.01% (2019) to 11% (2020) to 14% (2021). The most significant patient-level factors associated with increased telehealth utilization included nonrural residence and age ≤65 years. Among patients residing in rural settings, video visit utilization rates were significantly lower and phone visit utilization rates were significantly higher compared with patients from nonrural residences. Regarding provider-level factors, widening differences in telehealth utilization were observed at tertiary versus community-based practice settings. Increased telehealth utilization was not associated with duplicative care as per-patient and per-physician visit volumes in 2021 remained consistent with prepandemic levels. CONCLUSION We observed continuous expansion in telehealth visit utilization from 2020 to 2021. Our experiences suggest that telehealth can be integrated into cancer practices without evidence of duplicative care. Future work should examine sustainable reimbursement structures and policies to ensure accessibility of telehealth as a means to facilitate equitable, patient-centered cancer care.

Background: Multiple myeloma (MM) is the second most common hematologic malignancy, with 34,470 estimated new cases in 2022. High-dose therapy followed by autologous hematopoietic cell transplantation (auto-HCT) remains a standard treatment for MM even in the era of novel therapies. This is usually performed in hospital-based settings, either in the inpatient or outpatient units. Advanced Care at Home (ACH) represents a virtual hybrid hospital-at-home program that combines a virtual provider-staffed command center with a vendor-mediated supply chain capable of delivering high-acuity care in the comfort of the patients’ own homes. In our program, we used the existing ACH platform to deliver post-HCT care for recipients of auto-HCT. Patients and methods: Four patients (female = 2, 50%) with MM, with a median age of 60 (range, 40–74) years, were admitted to the inpatient Blood and Marrow Transplant (BMT) unit. The conditioning regimen consisted of melphalan 200 mg/m 2 , administered on day –2. All patients received stem cell infusion (day 0) in the inpatient setting, with a median dose of 3.64 (range, 2.92–8.22) × 10 6 /kg CD34 cells. Results: Patients were discharged to their homes after completing the infusion on day 0 or day +1 at the latest. Postinfusion care was provided by the ACH team in coordination with the BMT team. The median time intervals to absolute neutrophil count and platelet engraftment were 12 (range, 11–13) and 11 (range, 9–16) days, respectively. All patients were successfully discharged from the ACH program at a median of day +14 (range, day +14 to day +15). Conclusions: Our results highlight the feasibility of delivering post-HCT care for auto-HCT recipients in the home setting and confirm the generalizability of this approach.

e19501 Background: Relapsed and/or refractory (R/R) disease is observed in patients who receive CD19 targeting chimeric antigen receptor (CAR)-T cells to treat B-cell lymphoid leukemias and lymphomas. We generated a novel CAR, MC10029 that targets B-cell activating factor receptor (BAFF-R) to address this unmet medical need. Methods: We engineered a second-generation BAFF-R CAR (MC10029 CAR). The construct includes the single chain variable fragment (scFv) of our newly developed BAFF-R antibody with CD28 costimulatory and CD3ζ signaling domains. We confirmed MC10029 CAR-T cell antigen-specific activation with in vitro degranulation assays and a direct cytolytic assay. We used BAFF-R positive leukemia and lymphoma cell lines in both in vitro and in vivo models to further characterize MC10029 CAR-T cells, and finally, we enriched tumor primary cells from chronic lymphocytic leukemia (CLL) patients as a target for MC10029 CAR-T cells. In preparation for our Phase I clinical trial, we have manufactured three batches of CAR-T cells using a MC10029-encoding lentiviral vector produced under GMP conditions. The production batches of MC10029 CAR-T cells were evaluated for product quality with Viability, Identity and Potency as well as Safety from adventitious viral agents. Antigen specific cytotoxicity of the MC10029 CAR-T cells was confirmed using our standard degranulation assay. Results: MC10029 CAR-T cells elicited in vitro antigen-specific cytotoxicity against Nalm-6 cells, Z138 cells, MEC-1 cells, and a CD19 knock out Nalm-6 model designed to mimic CD19-negative R/R disease. We demonstrated in vivo antitumor effects of MC10029 CAR-T cells in NSG mice challenged with these same cell lines. We showed cytotoxicity of MC10029 CAR-T cells against CLL patients’ tumors. We also showed our quality control results to highlight our clinical trial trajectory. Conclusions: Novel MC10029 CAR-T cells showed broad utility against BAFF-R positive B-cell lymphoid malignancies in a series of in vitro, in vivo, and ex vivo models. With these robust data, we have moved forward to generate clinical grade MC10029 CAR-T cells using cGMP manufacturing and quality protocols in preparation of a MC10029 CAR-T cell Phase I clinical trial.

Abstract Black men are disproportionately affected by prostate cancer (CaP), with limited progress in closing the CaP care and survivorship gaps experienced by Black men compared to other racial/ethnic groups. Unfortunately, there is an uptick in CaP incidence rate in the United States (US) since 2014. As reported by the American Cancer Society, the rising CaP incidence rate indicates a shift towards higher grade and stage during diagnosis. The prostate cancer (CaP) disparities experienced by Black men in the US is a microcosm of the global burden of CaP seen in men of African ancestry. For example, the top ten countries leading CaP mortality in the world are all Black nations in Africa and the Caribbean. The complexity of CaP disparities and the need for a unique approach to better understand and address a complex chronic disease, such as CaP, underscores the need for consortium research that is multilevel, collaborative, translational, and global. Through the Department of Defense funding, we formed an inclusive Cancer Care Research Equity (iCCaRE) for Black Men Consortium to advance health equity and reduce disparities in CaP. Comprising CaP survivors, advocates, scientists, and clinicians, the iCCaRE for Black Men Consortium addresses structural, social and biological determinants of CaP among ethnically diverse Black men globally, including US Black men, West African immigrant men in the US and indigenous West African men. The overall goal of the iCCaRE consortium is to optimize CaP diagnosis experiences, treatment and survivorship based on the Science of Survivorship (SOS). Our central hypothesis is that improving social-determinants of health (SDOH) factors, CaP care and survivorship (CaPCaS)-related factors and mediating biological factors will lead to an improvement in patient-reported outcomes (PROs). This presentation will highlight the structural inequities, societal injustices and biological determinants found to be associated with CaP care and survivorship among Black men. Additionally, we will present the use of Community Living Lab (CoLLab) Health System approach to address inequity in minoritized and marginalized communities. Citation Format: Folakemi Odedina, Roxana Dronca, Kimlin Ashing, Ernest Kaninjing, Solomon Rotimi, Che Ngufor, Arnold Merriweather, iCCaRE Consortium. Science of prostate cancer care and survivorship in black men: Structural, social and biological determinants [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr IA007.

Abstract Oncologic viruses (OV) can induce tumor death through both direct oncolysis and immune-mediated destruction. Our study investigates the use of a novel OV with a Vesicular Stomatitis Virus (VSV) vector modified to express interferon-beta (IFN-b) and Tyrosinase Related Protein 1 (TYRP1) (VSV-IFNb-TYRP1). VSV is an attractive vector since humans are not naturally infected with VSV; thus, pre-existing immunity is minimal. IFN-b leads to increased T-cell responses and tumor cell apoptosis, while TYRP1, a melanocyte differentiation antigen, increases immunogenicity of the therapy. We conducted a Phase 1 clinical trial with a 3+3 design in patients with metastatic uveal melanoma. VSV-IFNb-TYRP1 was injected into a liver metastasis under image guidance, then administered on the same day as a single intravenous (IV) infusion. IV doses started at dose level (DL) 1 1 × 1010 TCID50, then escalated to DL2 3 × 10 10, DL3 1 × 1011, and DL4 3 × 1011. The dose delivered intratumorally (IT) varied based on the IV dose. The primary endpoints were safety and maximum tolerated dose (MTD). Efficacy was a secondary endpoint. Correlative studies focused on understanding viral pharmacokinetics (PK) and immunological responses induced by VSV-IFNb-TYRP1 therapy. Twelve patients with previously treated metastatic uveal melanoma were enrolled. Median follow up was 19.1 months. Four DLs were evaluated with one patient at DL4 experiencing dose limiting toxicities (DLTs), including decreased platelet count (grade 3), increased aspartate aminotransferase (AST), and cytokine release syndrome (CRS). Non-DLTs at DL4 were fatigue, fever, CRS, hematological toxicities (decreased platelets and lymphocytes), and AST elevation. Four patients had stable disease (SD) and 8 had progressive disease (PD) as their best response. ELIspot data show that three of the four patients with response to TYRP1 also had a response to gp100, suggesting possible epitope spreading. These four patients received immune checkpoint inhibitor treatment as the next line of therapy, which led to clinical benefit for two patients. Our study evaluated VSV-IFNb-TYRP1 administered via IT and IV routes in a previously treated population of metastatic uveal melanoma patients and found no major safety events. Although there were no clear objective responses to VSV-IFNb-TYRP1, dose-dependent immunogenicity to melanoma antigens was seen. While OV response alone is not sufficient for clinical benefit, the evidence of epitope spreading is encouraging. Future studies of VSV-IFNb-TYRP1 will evaluate combinations with other therapies. Citation Format: Katherine E. Smith, Adam Weisbrod, Carrie Strand, Jacob Allerd, Jose S. Pulido, Alysha Newsom, Lianwen Zhang, Nandakumar Packiriswamy, Heather Montane, Lisa Kottschade, Anastasios Dimou, Yiyi Yan, Markovic Svetomir, Kah Whye Peng, Richard G. Vile, Matthew S. Block, Roxana S. Dronca. Phase I trial of vesicular stomatitis virus expressing human interferon beta and tyrosinase related protein 1 (VSV-IFNb-TYRP1) in metastatic ocular melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT207.

Abstract The day I received news of my prostate cancer diagnosis time paused for a minute. My heart was heavy, and my mind racing and my soul appeared to leave my body as the physician kept talking. I’m looking at this doctor and having internal conversations with myself about dying. My attention switched from listening to reflecting to Fred Sanford holding his heart and saying “Elizabeth, I am coming to join you”, but my wife was right next to me holding my hand. The embrace of our interlocked fingers without saying a word to one another assured both of us this too shall pass. My knowing I had support encouraged me to begin educating myself about the science of survivorship. The presence of prostate cancer resources was absent in my community. I began reading information online to grasp a better understanding of this disease. The information gained encouraged me to request a second opinion from another oncologist. I was amaze by the difference in opinion about treatment options. I felt the urge to identify and specifically speak with other Black men going through this process. Everywhere I looked for support groups felt like removing my hands from pocket and watching lent flee from my fingers. What did I do? I registered my own prostate cancer support group with the state of Florida. The group grew from a few to 20 Black men across major metropolitan cities in Florida. These group meetings extended to men leading groups in their communities. I joined the Prostate Health Education Network as the Regional Ambassador to promote prostate awareness and clinical trials. My advocacy presence in the state of Florida led to Dr. Odedina and I crossing paths to champion elimination of prostate cancer health disparities for Black men. I am a Citizen Scientist in the lab of Dr. Odedina working on the inclusive cancer care and research equity for Black men consortium. I have co-authored publications, co-presented at conferences, served on research projects, and contributed to grant funding totaling over $25 million as a citizen scientist. Currently working on a Department of Defense funded grant focusing on the point of prostate cancer diagnosis. The project has completed several events to dispel myths about participation in clinical research while discussions about early detection is vital to improve survivorship. The reward from this work is knowing I am helping create spaces for Black men never to travel this journey alone. I believe men appreciate having a patient supporter but require fellowship with men who have traveled the road to gain navigational insights on how to maneuver across this terrain. Citation Format: AJ Merriweather, Dottington Fullwood, Che Ngufor, Jennifer Crook, Emelina Asto-Flores, Parisa Fathi, Roxana Dronca, Shannon Pressey, Folakemi Odedina. Early detection saves lives: I survived, and you can too— Any day above ground is a good day [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 727.

Abstract Background: Black men continue to be disproportionately affected by prostate cancer incidence and mortality as compared to their White counterparts, despite worldwide declining prostate cancer diagnosis rates. This complex phenomenon remains poorly understood, especially at the point of a prostate cancer diagnosis. Newly diagnosed Black men report initial feelings ranging from being “shocked,” to “receiving a death sentence,” and both an ineptness of asking questions and a reliance on physicians for treatment options due to lack of knowledge. The psychological distress from prostate cancer uncertainties affects health management and treatment decisions, though it is unclear to what extent the role of social determinants of health factor in making informed healthcare decisions. Aim: In this scoping review, we examined the influence of the social determinants of health at point of prostate cancer diagnosis among Black men seeking to make an informed decision about their treatment plans. Methods: We followed the methodological framework: the Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR). Five electronic databases, Emabase, Pubmed, PsycInfo, Scopus, and Web of Science were searched for quantitative and qualitative primary studies from the period 2005 until March 2022. Two authors independently screened titles and abstracts, and full texts, against predefined criteria: empirical research, post 2000, in English-language peer-reviewed journals; participants included Black prostate cancer survivors and research explored social determinants of health at point of prostate cancer diagnosis. Studies were quality assessed for data charting. Results: The search yielded 283 studies, with 45 included studies for synthesis. Traditional social determinants of health were frequent. However, identification of themes such as social support, masculinity and stigma, fear of abandonment by medical staff, and cost of diagnostic procedures were prominent determinants. Notably, sub-themes emerged that included coping factors such as emotional distress, perceptions of normalcy, and poor prostate cancer knowledge. Conclusion: Understanding the social determinants of health impact on Black men, especially at point of prostate cancer diagnosis will allow survivors, physicians, and researchers to work at solving these health disparities. Citation Format: Dottington Fullwood, AJ Merriweather, Che Ngufor, Deidre Pereira, KC Balaji, Roxana Dronca, Gerardo Colon-Otero, Jennifer Crook, Parisa Fathi, Emelina Asto-Flores, Shannon Pressey, Folakemi Odedina. iCCaRe: Social determinants of health navigation, psycho-oncology, and emotional support for Black prostate cancer survivors: Review of current practices. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4371.

Abstract The immune responses to anti-PD-1 therapy in cancer patients are not completely defined due to lack of reliable biomarkers that identifies responsive and functional T cells. Bim, a molecule of the Bcl-2 family, was recently identified as a downstream signaling molecule of PD-1 pathway in CD8+ T cells and has both pro-apoptotic and effective roles in CD8 T cells. Our clinical data shown that high level of Bim in CD8+ T cells (before checkpoint blockade) was predictive of response in metastatic melanoma whereas in colorectal cancer, low level of Bim was associated with treatment response. Using co-immunoprecipitation, high resolution microscopy and FRET we identified ANT2 (Adenine Nucleotide Translocase 2, an inner membrane protein of mitochondria) as a protein interacting with Bim. Accordingly, we found CD8+ T cells with low and high mitochondrial potential demonstrated different ANT2/Bim ratio, and high ANT2/Bim ratio fall in effector T cells with low mitochondrial potential but high cytotoxic activity. Given the pro-survival of ANT2, our results indicate that ANT2 may function to balance the pro-apoptotic and effective role of Bim in mitochondria in order to preserve effector T cells before contraction. Understanding the molecular mechanism of Bim and ANT2 interaction in CD8+ T cells may provide a novel marker to identify resilient CD8+ T cells responsive to anti-PD-1 therapy, and predict clinical response to the therapy.

Abstract Background: To date, the disparate burden of prostate cancer (CaP) in Black men (BM) is still poorly understood. More disconcerting is the limited access to effective, culturally tailored behavioral interventions to support BM diagnosed with CaP, especially at the point of prostate cancer diagnosis (PPCD). From the PPCD, the transition to CaP survivorship can be mentally and physically trying, especially for those lacking emotional and financial support. It is important to provide psycho-oncology support, address social determinants of health (SDOH) and make emotional support available to ethnically diverse BM at the PPCD. We are addressing the CaP disparities experienced by BM at the PPCD through the Inclusive Cancer Care Research Equity (iCCaRE) for Black Men Consortium. Aim: As part of the iCCaRE for Black men Consortium, the specific aim of our project is to develop a PPCD-based Augmented Reality (AR) intervention program, the iCCaRE PPCD Virtual Robot Assistant (ViRA). The ViRA is based on the established efficacy of six CaP care and survivorship (CaPCaS) video interventions, and will support BM at the PPCD. Methodology: The efficacy of six CaPCaS videos were established through formative research that included 17 BM in Florida. Based on pre- and post-test design, data were collected from participants using a structured survey tailored to each CaPCaS intervention: Prevention, Detection, Diagnosis, Treatment, Survivorship and Advocacy form. Following the efficacy study, the iCCaRE PPCD ViRA was proposed as one of five iCCaRE Science of Survivorship (S.O.S) projects to improve the quality of life of BM. Results: Most of the participants for the efficacy study reported that they were: US-born BM; married; college educated; earn less than $60,000; retired; have health insurance; have annual health examination; have a regular doctor; and were screened within the last year. The CaPCaS videos were found to be efficacious in improving attitude towards CaP screening, beliefs about CaP screening, perceived behavioral control and CaP knowledge. Participants also rated the quality of the videos high and expressed high satisfaction with the videos. We are currently in the development phase of the PPCD iCCaRE ViRA, which is based on behavioral science and health communications model. The ViRA will provide SDOH navigation services, psycho-oncology support and emotional support. The acceptance and usability of the iCCaRE ViRA will be established at urology clinics in Florida as part of the iCCaRE Consortium HEROICA Phase I study. We will test the central hypothesis that improving SDOH factors and CaPCaS-related factors will lead to an improvement in patient reported outcomes. Conclusion: We established the efficacy of the CaPCaS interventions in supporting BM across the CaP care continuum. The iCCaRE ViRA under development will target intervention at the PPCD and deliver a smart and connected personalized AR-enabled intervention system that will positively impact CaP diagnosis experience of BM. Citation Format: Folakemi Odedina, Che Ngufor, Arnold Merriweather, Deidre Pereira, Jennifer Crook, Fathi Parisa, Roxana Dronca, Ernest Kaninjing, Solomon Rotimi, Kimlin Ashing, Manisha Salinas, Sha’Reff Rashad, John McCall, Ebenezer Erefah, Ayinde Yahaya, Wes Sholes. A point of prostate cancer diagnosis (PPCD) Virtual Robot Assistant (ViRA) intervention for newly diagnosed Black men: An iCCaRE consortium for prostate cancer in Black men project [abstract]. In: Proceedings of the 15th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2022 Sep 16-19; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr B028.