Derebail, Vimal K.
https://orcid.org/0000-0002-7662-7497
Mayo Clinic
University of North Carolina at Chapel Hill
Citations 2
Mechanistic basis of the acute safety profile of rese-cel, an autologous CD19-CAR T, in patients with autoimmune disease treated in four ongoing phase 1/2 clinical trials
Volkov, J., Thompson, Dan , Nezhad, Fatemeh Hadi, Braccia, Domenick J. , Fumanak, Thomas, Werner, Mallorie, Vorndran, Zachary, Williams, Jazmean K. , Cicarelli, Justin, Kobulsky, Danielle R. , Lam, Quynh, Little, Courtney, White, Yvonne, Sheikh, Saira Z. , Abedi, Mehrdad , Sise, Meghan E. , Palma, Christopher , Edens, Cuoghi , Kosuri, Satyajit, Elgarten, Caitlin W. , Burnham, Jon M. , Ulane, Christina, Mozaffar, Tahseen , Chahin, Nizar, Wilfong, Erin R., Khanna, Dinesh, Ghosh, Monalisa , Shah, Ankoor R. , Hogan, Jonathan J., Estremera, Rebecca, Tummala, Raj , Chang, David , Binder, Gwendolyn K., Basu, Samik , Khanna, Dinesh , Khanna, Dinesh , Nunez, Daniel, Thompson, Dan, Nezhad, Fatemeh Hadi, Stadanlick, Jason E. , Ishikawa, Larissa Lumi Watanabe , Ellis, Alexandra, Flanagan, Steve, Little, Courtney, White, Yvonne, Derebail, Vimal K. , Grover, Natalie S. , Gulati, Gaurav, Abedi, Mehrdad, Frigault, Matthew J. , Reagan, Patrick Michael , Reshef, Ran , Naddaf, Elie , Wilfong, Erin, Shah, Ankoor, Hogan, Jonathan J. , Chang, David
Blood | December 5, 2025 | Volume: 146 | Issue: Supplement 1 | Pages: 2336-2336
Abstract Introduction: Autologous CD19 CART therapies have been utilized across a wide range of B cell driven autoimmune diseases (AD), including systemic lupus erythematous (SLE), idiopathic inflammatory myopathies (IIM), systemic sclerosis (SSc), & myasthenia gravis (MG). To date, a number of autologous CD19-CART therapies have delivered durable drug free responses in AD patients. However, the safety profile of autologous CD19-CART therapies across different AD has yet to be fully explored. This is especially true for CRS & ICANS. Here, we provide novel insight into the mechanism underlying the safety profile of resecabtagene autoleucel (rese-cel) an autologous CD19 41BBz CART therapy across four separate Phase I/II clinical trials in SLE, IIM, SSc, & MG. Objectives: The primary objective of each trial is safety & tolerability of rese-cel at Day 29. Key secondary objectives include changes in clinical scores & use of immunomodulatory agents. Key translational assessments include CART cell pharmacokinetics (PK), impact on peripheral B cell populations (pharmacodynamics), & serum cytokine levels. Methods: 19 Patients (data cutoff: 6/2/2025 SLE; 5/6/2025 IIM, SSc, and MG), with active disease refractory to standard of care have been treated across 4 Phase I/II clinical trials in SLE (8 patients; NCT06121297), IIM (8 patients; NCT06154252), SSc (2 patients; NCT06328777), & MG (1 patient; NCT06359041). All patients were treated with a single weight-based infusion of rese-cel at a dose of 1 x 106 cells/kg following lymphodepletion (flu 25 mg/m2/d on Days -5, -4, & -3, & cy 1,000 mg/m2/d on Day -3). All non-glucocorticoid immunomodulatory agents were stopped prior to lymphodepletion. Glucocorticoids were tapered post-infusion. Patients were not given prophylactic tocilizumab pre-infusion. Translational assessments were determined as follows: CART PK was evaluated by flow cytometry & dPCR; B-cell enumeration & phenotyping were evaluated by flow cytometry; & serum cytokines were evaluated via immunoassay. Results: Across all indications (19 patients), 7 episodes of CRS were observed (7/19). 6 of 7 patients experienced a Grade 1 CRS, & 1 patient had a Grade 2 CRS. 2 patients developed ICANS; 1 patient had a Grade 4 (previously presented at ACR Convergence 2024), & the other patient had a Grade 3. Both ICANS events were rapidly resolved without sequelae using standard therapy. These CRS and ICANS events differed across indications. In IIM, 4 of 8 patients experienced Grade 1 CRS and no patients experienced ICANs. In SLE, 2 patients experienced Grade 1 CRS and one developed Grade 4 ICANs. In SSC, 1 of 2 patients experienced Grade 2 CRS & the other experienced Grade 3 ICANS. In MG, no CRS or ICANS was observed. Rese-cel infusion products were ~ 66% transduced, with a mean CD4:CD8 ratio of 6. Post-infusion, peak CART expansion was observed on day 12 & the mean peak expansion was 89 cells/µL (SD +/- 214). B cells were rapidly depleted from peripheral blood post-infusion, with nadir occurring at 13 days & repopulation beginning at 62 days post-infusion on average. Re-emergent B cells were largely of the CD24+CD38+ transitional naïve phenotype. Commensurate with B cell depletion, serum BAFF induction was observed, with a mean fold induction of 16 & mean peak level of 56,404 pg/µL (SD: +/- 45,547). Serum cytokines associated with CRS & ICANS; IFNg, IL6, & IL8 reached peak elevation on days 10, 9, & 10 respectively post-infusion. The mean peak elevation for IFNg, IL6, & IL8 were 232 pg/ µL (SD: +/- 320), 44 pg/ µL (SD: +/- 60), & 80 pg/ µL (SD +/- 73), respectively. Conclusion: Rese-cel appears to be well tolerated in autoimmune patients with rates of CRS & ICANS of 37% & 11% across all autoimmune indications, respectively (SLE patients had a 25% CRS rate & 12.5% ICANS rate, IIM patients had a 50% CRS rate & 0% ICANS rate, SSC patients had a 50% CRS & 50% ICANS rate, & MG patients had a 0% CRS & ICANS rate). Notably, the frequency & severity of CRS appears to be low, with no CRS in 63% of patients (12/19) & most CRS events (6/7) being Grade 1. The lower frequency & severity of both CRS & ICANS events are likely correlated with the relatively modest induction of serum IFNg, IL6, & IL8 found in autoimmune patients post rese-cel weight-adjusted dose infusion. High BAFF levels reflect deep systemic B cell depletion. Together, these data support further support late-stage clinical development of rese-cel in autoimmune disease.
The longitudinal relationship between patient-reported outcomes and clinical characteristics among patients with focal segmental glomerulosclerosis in the Nephrotic Syndrome Study Network
Troost, Jonathan P. , Waldo, Anne, Carlozzi, Noelle E. , Murphy, Shannon L., Modersitzki, Frank , Trachtman, Howard , Nachman, Patrick H. , Reidy, Kimberly J. , Selewski, David T. , Herreshoff, Emily, Srivastava, Tarak, Gibson, Keisha L. , Derebail, Vimal K. , Lin, Jen Jar, Hingorani, Sangeeta, Sambandam, Kamalanathan K. , Athavale, Ambarish M., Reich, Heather N. , Adler, Sharon G. , Dell, Katherine M., Appel, Gerald B., Wang, Chia-shi , Kaskel, Frederick J. , Lafayette, Richard , Atkinson, Meredith A. , Kretzler, Matthias , Lemley, Kevin V. , Brown, Elizabeth , Meyers, Kevin , Gadegbeku, Crystal A., Holzman, Lawrence B. , Jefferson, Jonathan Ashley, Tuttle, Katherine R, Singer, Pamela, Hogan, Marie C. , Cattran, Daniel C., Network, the Nephrotic Syndrome Study, Dell, K, Schachere, M., Lemley, K, Whitted, L, Haney, Connie J, Gurusinghe, Sayuri , Toledo, Michelly Louise Sartório Altoé, Greenbaum, L, Wang, C, Lee, B, Nast, Cynthia C. , Page, J La, Stroger, John H, Itteera, M. , Neu, Alicia M. , Boynton, Sara Ashley, Chernitskiy, Vladimir, Reidy, K, Kopp, J, Castro-Rubio, E, Brede, E, Blake, J. Thomas, Modersitzki, F, Lafayette, R, Mehta, K. , Johnstone, Duncan B., Pfeffer, Zoe, Cattran, D, Hladunewich, M, Reich, H, Ling, P., Romano, M, Barisoni, L, Bidot, Carlos, Kretzler, M, Williams, A, Pitter, R, Gibson, K, Grubbs, S, Froment, Anne, Holzman, L, Kallem, K., Cerecino, F J, Johnson, N, Jefferson, A, Tuttle, Katherine R. , Klepach, K, Kelton, M, Cooper, Ann , Lin, J J, Spainhour, Mitzie, Gray, S, Barisoni, L, Gillespie, B, Gipson, D, Holzman, L, Mariani, Laura , Song, Peter X.‐K. , Kincaid, Colleen, Lienczewski, Chrysta, Mainieri, T, Williams, Anna , Ávila-Casado, Carmen , Bagnasco, Serena M. , Gaut, Joseph P. , Hewitt, Stephen M. , Palmer, M, Rosenberg, A, Royal, Virginie , Barisoni, L, Nast, C, Roy, Cindy N., Urv, T, Dell, K, Greenbaum, L, Lee, B, Page, J La, Stroger, John H, Reidy, K, Kopp, J, Brede, E, Modersitzki, F, Lafayette, R, Gadegbeku, C, Cattran, D, Hladunewich, M, Reich, H, Romano, M, Pitter, R, Gibson, K, Cerecino, F J, Jefferson, A, Lin, J J, Gray, S, Kretzler, M, Gillespie, B, Gipson, D, Mariani, L, Mainieri, T, Williams, A, Mariani, L, Palmer, M, Rosenberg, A, Barisoni, L, Urv, T, Wang, Chia-Shi , Tuttle, Katherine R , Hogan, Marie C , Fornoni, Alessia , Fervenza, Fernando C. , Kopp, Jeffrey B. , Greenbaum, Larry A. , Sedor, John R. , Lieske, John C. , Srivastava, Tarak , Hladunewich, Michelle , Tuttle, Katherine R, Singer, Pamela S. , Barisoni, Laura , Gipson, Debbie S , Network, the Nephrotic Syndrome Study, Dell, K, Lemley, K, Greenbaum, L, Lee, B, Page, J La, Stroger, John H, Reidy, K, Kopp, J, Brede, E, Zhdanova, Olga A. , Modersitzki, F, Vento, Sandro , Lafayette, R, Cattran, D, Hladunewich, M, Reich, H, Romano, M, Barisoni, L, Bidot, C, Kretzler, M, Williams, A, Pitter, R, Gibson, K, Holzman, L, Cerecino, F J, Jefferson, A, Freedman, Barry I. , Lin, J J, Gray, S, Barisoni, L, Gillespie, B, Gipson, D, Holzman, L, Sampson, Matthew Gordon , Zee, Jarcy , Mainieri, T, Hodgin, Jeffrey B. , Palmer, M, Rosenberg, A, Thomas, D, Barisoni, L, Nast, C, Abbott, Kevin C. , Roy, C, Urv, T, Brooks, Philip John , Dell, K, Greenbaum, L, Lee, B, Page, J La, Stroger, John H, Reidy, K, Kopp, J, Brede, E, Modersitzki, F, Lafayette, R, Gadegbeku, C, Cattran, D, Hladunewich, M, Reich, H, Romano, M, Bidot, C, Pitter, R, Gibson, K, Cerecino, F J, Jefferson, A, Lin, J J, Gray, S, Kretzler, M, Gillespie, B, Gipson, D, Mariani, L, Mainieri, T, Williams, A, Mariani, L, Palmer, M, Rosenberg, A, Thomas, D, Barisoni, L, Roy, C, Urv, T, Troost, Jonathan P.
Clinical Kidney Journal | July 3, 2019 | Volume: 13 | Issue: 4 | Pages: 597-606
Abstract Background Understanding the relationship between clinical and patient-reported outcomes (PROs) will help support clinical care and future clinical trial design of novel therapies for focal segmental glomerulosclerosis (FSGS). Methods FSGS patients ≥8 years of age enrolled in the Nephrotic Syndrome Study Network completed Patient-Reported Outcomes Measurement Information System PRO measures of health-related quality of life (HRQoL) (children: global health, mobility, fatigue, pain interference, depression, anxiety, stress and peer relationships; adults: physical functioning, fatigue, pain interference, sleep impairment, mental health, depression, anxiety and social satisfaction) at baseline and during longitudinal follow-up for a maximum of 5 years. Linear mixed-effects models were used to determine which demographic, clinical and laboratory features were associated with PROs for each of the eight children and eight adults studied. Results There were 45 children and 114 adult FSGS patients enrolled that had at least one PRO assessment and 519 patient visits. Multivariable analyses among children found that edema was associated with global health (−7.6 points, P = 0.02) and mobility (−4.2, P = 0.02), the number of reported symptoms was associated with worse depression (−2.7 per symptom, P = 0.009) and anxiety (−2.3, P = 0.02) and the number of emergency room (ER) visits in the prior 6 months was associated with worse mobility (−2.8 per visit, P < 0.001) and fatigue (−2.4, P = 0.03). Multivariable analyses among adults found the number of reported symptoms was associated with worse function in all eight PROMIS measures and the number of ER visits was associated with worse fatigue, pain interference, sleep impairment, depression, anxiety and social satisfaction. Laboratory markers of disease severity (i.e. proteinuria, estimated glomerular filtration rate and serum albumin) did not predict PRO in multivariable analyses, with the single exception of complete remission and better pain interference scores among children (+9.3, P = 0.03). Conclusions PROs provide important information about HRQoL for persons with FSGS that is not captured solely by the examination of laboratory-based markers of disease. However, it is critical that instruments capture the patient experience and FSGS clinical trials may benefit from a disease-specific instrument more sensitive to within-patient changes.