Dronca, Roxana

Abstract Background: A recent report from the AACR has found that black men (BM) men have prostate cancer (CaP) death rates that are more than 2 times those for men of any other race or ethnicity. Yet, BM are less likely to receive cutting-edge, or even standard of care treatment compared to their white counterparts. Limited access to care, transportation, patient perception and medical mistrust, as well as cost of care are major contributing factors. Meeting patients where they are and offering treatment in or closer to their homes should help reduce psychological distress and increase access to care and treatment compliance. As part of the iCCaRE for Black men Consortium, we propose a PCHC model which leverages Mayo Clinic Advanced Care at Home (ACH) program and provides a package of care to support the administration of cancer therapy and/or supportive care/symptom management to CaP patients in their homes by specialist healthcare professionals. The objectives of our pilot study are to understand patients’ choice of therapy in choosing the place of treatment and to evaluate the feasibility and impact of PCHC on clinical outcomes, as well as patient reported-outcomes (PRO) and health related quality of life (HQOL). Methodology: For Aim 1, structured questionnaires are used to assess patient preference for location of therapy, at the infusion center or in the home, as well as perceived difficulties and advantages; follow up qualitative data will be collected through semi-structured interviews to capture patients’ thoughts, feelings, attitudes, and questions towards cancer treatments being administered at home versus in a hospital setting. Aim 2 is an observational study of BM with advanced CaP who are participating in a pragmatic, practice-based randomized clinical trial to track acceptability by and impact of home administration of cancer directed or supportive therapy. Results: For Aim 1, data is used to identify themes regarding perceived advantages and concerns of PCHC and inform our understanding of the proportion of patients who are willing to receive and would benefit from this level of care at home. For Aim 2, the following outcomes are evaluated: (a) time to first ER visit and to first hospitalization; (b) HRQoL and quality-adjusted survival; (c) patient satisfaction and compliance, including home time, adherence with symptom self-reporting and compliance with treatment, level of comfort interacting with the care team by phone or tablet, ability to reach a team member for questions or concerns; (d) cost, including out of pocket cost for patients. Conclusion: Our project will provide data on patient understanding and acceptability of cancer care at home and strategies for overcoming cancer care delivery disparities and barriers of access to care for underserved communities. The expected outcome of our project is that PCHC intervention will positively impact CaP treatment, patients’ access and experience with healthcare by developing a new concept of closer-to home cancer care delivery that will reach more patients in underserved communities. Citation Format: Roxana Dronca, Rohit Rao, Michael Maniaci, Folakemi Odedina, Ernest Kaninjing, Kimlin Ashing, Solomon Rotimi, Manisha Salinas, Sha’Reff Rashad, Arnold Merriweather, John McCall, Ebenezer Erefah, Ayinde Yahaya. Feasibility of patient-centered home care (PCHC) to reduce disparities in Black men (BM) with advanced prostate cancer (CaP): 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 B046.

Abstract Background: Sub-Saharan African immigrants (SSAI) in the United States (US) constitute one of the fastest-growing segments of the immigrant population. Between 2010 and 2018, the SSAI population in the US increased by 53%, significantly outpacing the 12% growth rate for the overall foreign-born population in the US during that time frame. For the purposes of this study, we define SSAI as the 2 million individuals living in the US originally from the region of the African continent located south of the Saharan desert. Despite their growing numbers, little is published about the extent to which SSAI adapt to health behaviors more common in the US or remain immersed in the values, beliefs and practices reflective of their country of origin. Importantly, no study has comprehensively examined the social determinants of health factors among this population and its influence on health-seeking behaviors and decision-making regarding prostate cancer care and treatment options. This study employs the social determinant of migrant health framework to examine the impact of immigration on the health-seeking behaviors of SSAI including informed-decision making, psychosocial effects and coping mechanisms. This study will fill the void of research studies that link social determinant of health and immigration among SSAI. Methods: Grounded theory will guide the study design that include in-depth interviews to document the experiences of SSAI relative to health seeking behaviors, care, and treatment. We explore differences and similarities among participants based on country or region of origin in Africa. We employ the social determinants of migrant health framework to better understand the needs of SSAI prostate cancer survivors in the United States and how to effectively support these survivors. Results: We will present findings based on preliminary interviews conducted with SSAI prostate cancer survivors recruited from Florida or Minnesota. Additionally, we will report on the development of a SSAI social determinant of migration model that explains individual and structural factors that impact the health-seeking behaviors and coping mechanisms among this population. We will provide new understanding about specific social determinant of health factors that can be addressed in intervention studies among SSAI in the United States. Conclusion: This study examines the full range of racial, social, environmental, behavioral and structural factors that SSAI prostate cancer survivors experience. It will illuminate the decision-making process and overall quality of care among this understudied population. Citation Format: Ernie Kaninjing, Gladys Asiedu, Mary Ellen Young, Ebenezer Erefah, Folakemi Odedina, Roxana Dronca, Kimlin Ashing, Solomon Rotimi, Che Ngufor, Arnold Merriweather, Jennifer Crook, Manisha Salinas, Parisa Fathi, Sha’Reff Rashad, John McCall, Ayinde Yahaya. The iCCARE consortium for prostate cancer in Black men: Grounded theory study of the social determinant of health factors among African immigrant men diagnosed with prostate cancer [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 B050.

Abstract Background: Black men across the world continue to bear the burden of prostate cancer (PCa). Although several factors account for this, studies have demonstrated that the adaptive constitutive biological factors associated with African ancestry contribute to the risk of disease development, disease aggression, and poor disease outcomes in Black men. However, the limited inclusion of Blacks in cancer biology studies limits the understanding of the extent to which biology influence outcomes among Blacks. Furthermore, beyond White-Black dichotomous disparity, there exists an under-exploited within-group geographical and ancestral disparities in the burden, clinical presentation, and outcomes of PCa among Black men globally. Aside from urological and sexual problems, Black PCa survivors experience poor mental health, with a concomitant reduction in the quality of life and overall survival. Hence, improving the overall well-being of PCa survivors requires an understanding of the biological determinants of mental health among diverse groups of Black PCa survivors. Methods: Structured questionnaires are being used to access fatigue, pain, depressive symptoms, health-related quality of life, and PCa-specific symptoms burden among within a cohort of ethnically diverse Black PCa survivors in Africa. This is linked with the salivary biomarkers of inflammation, hypothalamic-pituitary-adrenal axis activity, and tryptophan-kynurenine pathway in our studies population. Results: Data from fifty PCa survivors across different African ethnic groups (including, Yoruba, Igbo, Hausa) will be presented. This study will measure biological variables (e.g, inflammatory markers, cortisol, tryptophan, kynurenine, and serotonin) and survivors self-reported (e.g. health-related quality of life and psychoneurological symptoms) measures to better examine the interconnectedness between cancer-associated biomarkers and poor mental health. Conclusion: This study will lay an essential foundation for understanding the extent to which cancer associated-biological determinants contribute to the poor mental health of PCa survivors, unravels the within-group disparities in the mental health of Black PCa survivors, establish the contribution of genetics to poor mental health in Black PCa survivors and provide the opportunity for pharmacogenomic intervention that will improve the quality of life. Citation Format: Solomon O. Rotimi, Folakemi Odedina, Roxana Dronca, Kimlin Ashing, Ernest Kaninjing, Che Ngufor, Arnold Merriweather, Jennifer Crook, Manisha Salinas, Fathi Parisa, Sha’Reff Rashad, John McCall, Ebenezer Erefah, Ayinde Yahaya. Investigating the biological determinants of poor mental health among ethnically diverse Black prostate cancer survivors: 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 A045.

Abstract Background: The prostate cancer (CaP) disparities experienced by Black men (BM) in the US is a microcosm of the burden of CaP seen in BM globally. 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. In response to this need, we brought together CaP survivors, advocates, scientists and clinicians to form the inclusive Cancer Care Research Equity (iCCaRE) for Black Men Consortium. Aim: Our overall goal is to optimize CaP diagnosis experiences, treatment and survivorship based on the Science of Survivorship (S.O.S). Our primary aim was to develop a consortium co-led by CaP scientists and survivors with multiple S.O.S research projects supported by research cores/services across multiple institutions. Methodology: The consortium was developed to comprise multiple individuals with complementary expertise and resources working collaboratively to achieve the common purpose of eliminating CaP disparities globally. Building on the expertise, resources, and relationships of collaborating CaP investigators, survivors and advocates, the iCCaRE Consortium was proposed to “advance health equity and reduce disparities in CaP” by studying the within-group differences among ethnically diverse BM and comparing US-born BM to their ancestral populations, including West African immigrant men in the US and indigenous West African men. Results: Through the Department of Defense Health Equity Research and Outcomes Improvement Consortium (HEROIC) Award, the iCCaRE Consortium was launched in 2022. There are five pilot projects (PPs), each co-led by a scientist PI and community PI: PP1 will plan and develop a Virtual Robot Assistant (ViRA) that will provide SDOH navigation services, psycho-oncology support and emotional support for BM newly diagnosed with CaP. PP2 will develop and analyze the impact of a patient-centered home cancer care system on health-related Quality of Life (HRQOL), access to healthcare, and PROs. PP3 will plan and develop a ViRA to improve HRQOL in Black CaP survivors. PP4 will employ the social determinants of migrant health framework to understand and address the needs of sub-Saharan African immigrant CaP survivors. PP5 will explore how biological factors induced by cancer cells contribute to poor mental health of CaP survivors. The PPs are supported by an Administrative Core, Translational Research & Clinical Intervention Service, Data Management and Analytics Services, Partnership Engagement Services, Pathology Resource & Biospecimen Core, Methodology and Measures Services and Digital Health & Human Services. Conclusion: The iCCaRE Consortium will “improve HRQOL to enhance outcomes and overall health and wellness for those impacted by CaP” by developing and implementing Artificial Intelligence interventions that address social determinants of health, psycho-oncology support and emotional support for newly diagnosed CaP patients. Citation Format: Folakemi Odedina, Roxana Dronca, Kimlin Ashing, Ernest Kaninjing, Solomon Rotimi, Che Ngufor, Arnold Merriweather, Jennifer Crook, Manisha Salinas, Fathi Parisa, Sha’Reff Rashad, John McCall, Ebenezer Erefah, Ayinde Yahaya. Addressing prostate cancer disparities through the Inclusive Cancer Care Research Equity (iCCaRE) for Black men consortium [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 A042.

Abstract Markers of immune related adverse events and response in patients treated with immune checkpoint inhibitors (ICI) may shed light into ICI resistance, T cell exhaustion and other combinatorial therapies. The elevated levels of these biomarkers have potential to predict if PD-1 or PD-1/CTLA-4 antagonist combination will be effective in a certain Melanoma patient. Therefore, it may potentially guide healthcare providers to change treatment plans. In this study, the ICI treatments we focused on were PD-1 or combination of PD-1/CTLA-4 blockades. The measurement of the biomarkers was conducted at Mayo Clinic, from serum samples obtained in 2 time points, pre-treatments and 2–3 months after the first ICI treatments. Validated IVD kits were used per manufacture’s instruction. Biomarkers could be measured using stored frozen serum samples according to the instructions on how the biomarkers will be measured. We investigated 13 biomarkers in the sera of 76 melanoma patients who received immune checkpoint therapies. The biomarkers tested were, Human ELAFIN ELISA, Human IL-18 ELISA, Reg3α + Universal kit, Anti-Nuclear Antibody Test System, FLUORO AID-1 Test for anti-mitochondrial antibodies, anti-smooth muscle antibodies and anti-parietal cell antibodies, Anti-MDA5 ELISA Kit, Anti-synthetase ELISA Skin, Antineutrophil cytoplasmic antibodies MPO-ANCA ELISA, Antineutrophil cytoplasmic antibodies PR3-ANCA ELISA, Dsg1, Dsg3 ELISA, BP180, BP230, type-VII collagen. When compared with the samples obtained before treatments, IL-18 levels significantly elevated (p value < 0.0001) in post treatment samples of non-responders. Further studies are needed to confirm if elevated IL-18 contribute to the biology of resistance to ICI therapies. Supported by MBLI

Abstract The immune response to anti-PD-1 therapy in cancer patients is not completely defined due to lack of reliable biomarkers that can determine T cell function. Bim, a member of the Bcl-2 family, was recently identified as a downstream signaling molecule in the PD-1 pathway. Within CD8 T cells, Bim appears to have a dual function, and can be pro-apoptotic or promote effector activity. Our clinical data has shown that high levels of Bim in CD8 T cells are predictive of response to anti-PD-1 therapy in metastatic melanoma whereas in colorectal cancer, a low level of Bim is associated with treatment response. Thus, we sought to determine what molecular partners might influence the role of Bim. Using co-immunoprecipitation, high resolution microscopy and FRET we identified ANT2 (Adenine Nucleotide Translocase 2), an inner membrane protein of mitochondria, as a protein that interacts with Bim. Accordingly, we found CD8 T cells with low and high mitochondrial potential demonstrated different ANT2/Bim ratios, and a low ANT2/Bim ratio was present in effector T cells with low mitochondrial potential but high cytotoxic activity. Given the pro-survival function of ANT2, our results indicate that ANT2 may balance the pro-apoptotic and effector roles of Bim in mitochondria in order to preserve effector T cells before contraction. Understanding the molecular mechanism of Bim and ANT2 interactions in CD8 T cells may provide a novel marker to predict clinical response to anti-PD-1 therapy.

Abstract We have observed Th2 polarization in patients with metastatic malignant melanoma. We hypothesized that changes in the immune system with age may parallel changes we have seen in patients with cancer. We analyzed the peripheral blood of 389 healthy blood donors. We profiled T cell subsets in 389 of the subjects, and antigen-specific tetramers for CMV, influenza and MART-1 in 58 of the subjects. We used a cytokine multiplex to analyze 42 cytokines in 95 of the subjects. We observed significant increases in CD4+ Th2 cells, and decreases in CD3+ T cells, cytotoxic T cells and helper T cells with age. There were fewer CMV-, influenza- and MART-1- specific naïve and CD8+ T cells with age. There were also significant increases in MCP-1 and RANTES with age. We observed differences between males in females in their cytokine profiles in their 20-40’s but not in their 50-60’s. In summary, we have found that aging is associated with an increase in CD4+ Th2 cells and concomitant decreases in total T cell count, cytotoxic T cells and helper T cells. Furthermore, aging is associated with increases in MCP-1 and RANTES. Females had different cytokine profiles than males before menopause, but not after.

10588 Background: Detection of pathogenic germline variants (PGVs) has implications for cancer screening, prognostication, treatment selection, clinical trial enrollment and family testing. Published guidelines provide indications for PGV testing, determined by clinical and demographic factors, but these leave a significant number of cases missed by guideline-directed testing (incremental PGV). We have previously shown that 50% of patients with PVGs would not have been detected with guideline-based testing alone. In this project, we aimed to determine the feasibility and generalizability of this approach within a more racially/ethnically diverse cohort from a community cancer practice. Methods: We completed a prospective study of proactive germline genetic sequencing among patients with solid tumor malignancies at a community-based oncology practice in downtown Jacksonville, FL between June 2020, and September 2021. The patients were unselected for cancer type, stage, family history, race/ethnicity, and age. PGVs identified using an 84-gene NGS platform were stratified by penetrance. National Comprehensive Cancer Networks (NCCN) guidelines were used to determine incremental PGV rates. Results: 221 patients were enrolled, median age 63.0 years, 21.7% male. 56.6% of patients were white (non-Hispanic), 32.6% were black/African American, 5.4% were Hispanic. 39.8% of patients were commercially insured, 52.4% insured by Medicare/Medicaid and 2.7% uninsured. The cohort was comprised predominantly of breast cancer (61.5%), lung cancer (10.4%) and colon cancer (7.2%) patients. A total of 27 PGVs were identified in 23 patients. We found no significant difference in the rate of PGVs based on race/ethnicity. The overall rate of variants of uncertain significance (VUS) was numerically higher in black/African American patients (61.1%) compared with other ancestry (45%). 13 of 23 (56.5%) patients with detected PGVs did not meet NCCN guidelines for germline genetic screening (incremental PGVs). Conclusions: This prospective study found that universal multi-gene panel testing among patients from a racially/ethnically diverse cohort from a community cancer practice was associated with an increased detection of heritable variants with treatment implications over the predicted yield of targeted testing based on guidelines. This study is the first to evaluate this approach in an exclusively community-based practice. Clinical trial information: NCT04456140.

Abstract Cytotoxic CD8+ T cells (CTL) are a crucial component of the immune system notable for their ability to eliminate rapidly proliferating malignant cells. However, the T-cell intrinsic factors required for human CTLs to accomplish highly efficient antitumor cytotoxicity are not well defined. By evaluating human CD8+ T cells from responders versus nonresponders to treatment with immune checkpoint inhibitors, we sought to identify key factors associated with effective CTL function. Single-cell RNA-sequencing analysis of peripheral CD8+ T cells from patients treated with anti–PD-1 therapy showed that cells from nonresponders exhibited decreased expression of the cytolytic granule-associated molecule natural killer cell granule protein-7 (NKG7). Functional assays revealed that reduced NKG7 expression altered cytolytic granule number, trafficking, and calcium release, resulting in decreased CD8+ T-cell–mediated killing of tumor cells. Transfection of T cells with NKG7 mRNA was sufficient to improve the tumor-cell killing ability of human T cells isolated from nonresponders and increase their response to anti–PD-1 or anti–PD-L1 therapy in vitro. NKG7 mRNA therapy also improved the antitumor activity of murine tumor antigen–specific CD8+ T cells in an in vivo model of adoptive cell therapy. Finally, we showed that the transcription factor ETS1 played a role in regulating NKG7 expression. Together, our results identify NKG7 as a necessary component for the cytotoxic function of CD8+ T cells and establish NKG7 as a T-cell–intrinsic therapeutic target for enhancing cancer immunotherapy. See related article by Li et al., p. 154.

e17025 Background: PT-112 is a novel pyrophosphate-platinum conjugate that induces immunogenic cell death, reaches highest concentrations in bone (osteotropism), and synergizes with immune checkpoint inhibitors (ICIs) in preclinical models. Phase I studies in solid tumors, as monotherapy and in combination with PD-L1 inhibitor avelumab (“PAVE”), as well as in multiple myeloma as monotherapy have demonstrated that PT-112 is well-tolerated and active. We present updated safety and exploratory efficacy findings in a mCRPC sub-population treated with PAVE, including a cohort of patients at a lower-frequency dosing schedule. Methods: A total of 32 mCRPC patients (pts) received 800 mg of avelumab on days 1 and 15 of a 28-day cycle, of whom 18 received PT-112 on days 1, 8 and 15 at 200mg/m2 (n = 17) or 150 mg/m2 (n = 1); a separate cohort of 14 received PT-112 on days 1 and 15 at 300 mg/m2 (n = 13) or 200mg/m2 (n = 1). Results: Median age was 68 (range 47-87) and number of prior lines of therapy (Tx) was 7 (2-12), including prior platinum-containing therapy in 11 (34%) and ICI Tx in 9 pts (28%). Baseline grade 2 anemia was seen in 7 (22%) pts. The most common treatment-related adverse events (TRAEs) were anemia (47%) and thrombocytopenia (41%); 23 pts (72%) had ≥1 grade 3-4 TRAE, with no cases of bleeding, sepsis, or grade 5 TRAEs. Antitumor effects included 8 (25%) pts with a PSA reduction of ≥50% (PSA50); 5 (16%) were maintained through ≥1 follow-up. Of ten pts with RECIST-measurable disease, 3 had tumor volume reductions, one with a confirmed partial response (PR). Twenty-four (75%) pts experienced a reduction in serum alkaline phosphatase (ALP) (median reduction 15%), and improvement in patient-reported pain and quality of life was observed. For the 13 pts given 300 mg/m2 PT-112 bi-weekly, 7 (54%) had prior platinum-containing Tx and 4 (31%) had baseline grade 2 anemia. The most common TRAEs were anemia (69%) and thrombocytopenia (54%), with 11 (85%) pts having ≥1 grade 3-4 TRAE. Four pts (31%) had PSA50 reductions; 3 (23%) were maintained through ≥1 follow-up. Conclusions: PAVE is safe and generally well tolerated in mCRPC patients at the doses and schedules tested, providing meaningful antitumor effects in heavily pre-treated patients, including tumor volume, PSA and ALP reductions. Reductions in ALP may be indicative of anti-cancer activity at bone sites of disease. Although the sample sizes are small, the frequency of confirmed PSA50 responses and of grade 3-4 TRAEs was slightly higher in the group receiving biweekly 300 mg/m2 PT-112, and higher rates of TRAEs may be explained by higher baseline anemia and/or prior platinum Tx. Further clinical investigation of the combination of PT-112 plus ICIs in a less heavily pre-treated mCRPC population is warranted. A phase 2 study of PT-112 monotherapy in mCRPC is ongoing. Clinical trial information: NCT03409458.