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BiTE secretion from in situ-programmed myeloid cells results in tumor-retained pharmacology

J Control Release

2022 Christine Watson; Vaishali Inamdar; Matthias Stephan; Elena Sigmund; Stephanie Weaver; Sirkka Stephan; Fan Zhang; Siyang Hao

Bispecific T-Cell Engagers (BiTEs) are effective at inducing remission in hematologic cancers, but their use in solid tumors has been challenging due to their extreme potency and on-target, off-tumor toxicities in healthy tissue. Their deployment against solid tumors is further complicated by insufficient drug penetration, a hostile tumor microenvironment, and immune escape. To address these challenges, we developed targeted nanocarriers that can deliver in vitro-transcribed mRNA encoding BiTEs to host myeloid cells - a cell type that is actively recruited into the tumor microenvironment. We demonstrate in an immunocompetent mouse model of ovarian cancer, that infusion of these nanoparticles directs BiTE expression to tumor sites, which reshapes the microenvironment from suppressive to permissive and triggers disease regression without systemic toxicity. In contrast, conventional injections of recombinant BiTE protein at doses required to achieve anti-tumor activity, induced systemic inflammatory responses and severe tissue damage in all treated animals. Implemented in the clinic, this in situ gene therapy could enable physicians - with a single therapeutic - to safely target tumor antigen that would otherwise not be druggable due to the risks of on-target toxicity and, at the same time, reset the tumor milieu to boost key mediators of antitumor immune responses.

High End-of-Life Health Care Utilization in a Contemporary Cohort of Head and Neck Cancer Patients Treated with Immune Checkpoint Inhibitors

J Palliat Med

2021 Brittany Barber; George Laramore; Renato Martins; Upendra Parvathaneni; Keith Eaton; Neal Futran; Jay Liao; Christina Baik; Sylvia Lee; Jeffrey Houlton; Cristina Rodriguez; Rafael Santana-Davila; Qian (Vicky) Wu; Jenna Voutsinas

Background/Objective: End-of-life health care utilization (EOLHCU) is largely uncharacterized among patients with recurrent/metastatic head and neck squamous cell carcinomas (RMHNSCC), particularly now that immune checkpoint inhibitors (ICI) have been introduced to the treatment landscape. We examined this in a single-institution, retrospective study. Design/Settings: We utilized a database of deceased, ICI-treated RMHNSCC patients to obtain demographic and EOLHCU data, the latter of which included advanced care plan documentation (ACPD) and systemic therapy or emergency room (ER)/hospital/intensive care unit (ICU) admission within 30 days of death (DOD). This was compared with a cohort of deceased thoracic malignancy (TM) patients in an exploratory analysis. Multivariate analysis was performed to examine for association between patient factors (such as age, Eastern Cooperative Oncology Group (ECOG) performance status, or smoking status) and overall survival (OS); associations between the said patient factors and EOLHCU were also evaluated. This study was conducted at an academic, tertiary center in the United States. Results: The RMHNSCC patients (n = 74) were more likely to have ACPD (p < 0.01), an emergency department visit (p < 0.01), and/or hospital admission (p < 0.01) within 30 DOD relative to the TM group. There was no difference in ICU admissions, ICU deaths, or systemic therapy at end of life (EOL). The OS declined in association with ECOG performance status (PS) and smoking. No association was observed between patient factors and any EOLHCU metric. Conclusions: At our center, patients with ICI-treated RMHNSCC have higher rates of both ACPD and EOLHCU, suggesting high symptom burden and representing opportunities for further study into supportive care augmentation.

Empowering patients patients from within: Emerging nanomedicines for in vivo immune cell reprogramming

Semin Immunol

2021 Matthias Stephan

Currently, medicine lacks the ability to reprogram selected immune cells so they possess all the functions which, from a clinical standpoint, physicians might wish them to have. To solve this problem, scientists have been marrying concepts from materials science, immunology, and genetic engineering to develop novel nanotherapeutics that directly genetically reprogram immune cells inside the body. These products could address key limitations of existing ex vivo-engineered cell immunotherapies and substantially enhance patient access and outcomes. This review highlights the latest advances in this rapidly emerging biotech field and discusses challenges in translating these preclinical studies into successful clinical nanomedicines.

Immune cell topography predicts response to PD-1 blockade in cutaneous T cell lymphoma

Nat Commun

2021 Nirasha Ramchurren; Kimberly Smythe; Martin Cheever; Steven Fling; Robert Pierce

Cutaneous T cell lymphomas (CTCL) are rare but aggressive cancers without effective treatments. While a subset of patients derive benefit from PD-1 blockade, there is a critically unmet need for predictive biomarkers of response. Herein, we perform CODEX multiplexed tissue imaging and RNA sequencing on 70 tumor regions from 14 advanced CTCL patients enrolled in a pembrolizumab clinical trial (NCT02243579). We find no differences in the frequencies of immune or tumor cells between responders and non-responders. Instead, we identify topographical differences between effector PD-1+ CD4+ T cells, tumor cells, and immunosuppressive Tregs, from which we derive a spatial biomarker, termed the SpatialScore, that correlates strongly with pembrolizumab response in CTCL. The SpatialScore coincides with differences in the functional immune state of the tumor microenvironment, T cell function, and tumor cell-specific chemokine recruitment and is validated using a simplified, clinically accessible tissue imaging platform. Collectively, these results provide a paradigm for investigating the spatial balance of effector and suppressive T cell activity and broadly leveraging this biomarker approach to inform the clinical use of immunotherapies.

Severe cytokine release syndrome is associated with hematologic toxicity following CD19 CAR T-cell therapy

Blood Adv

2021 Nancy Miles; Cameron Turtle; Jenna Voutsinas; Jordan Gauthier; Alexandre Hirayama; Qian (Vicky) Wu; Merav Bar; David Maloney

CD19-targeted chimeric antigen receptor (CAR) T-cell therapy has demonstrated remarkable efficacy in patients with relapsed/refractory B-cell malignancies, however, is associated with toxicities including cytokine release syndrome (CRS), neurotoxicity, and impaired hematopoietic recovery. The latter is associated with high grade cytopenias requiring extended growth factor or transfusional support, potentially leading to additional complications such as infection or hemorrhage. To date, the factors independently associated with hematologic toxicity have not been well characterized. To address this, we retrospectively analyzed 173 patients who received defined-composition CD19 CAR T-cell therapy on a phase I/II clinical trial (NCT01865617), with primary endpoints of absolute neutrophil count (ANC) and platelet count at day-28 following CAR T-cell infusion. We observed cumulative incidences of neutrophil and platelet recovery of 81% and 75% respectively, at 28 days post-CAR T-cell infusion. Hematologic toxicity was noted in a significant subset of patients with persistent neutropenia in 9% and thrombocytopenia in 14% at last follow-up. Utilizing debiased LASSO regression analysis for high-dimensional modeling and considering patient-, disease-, and treatment-related variables, we identified increased CRS severity as an independent predictor for decreased platelet count and lower pre-lymphodepletion platelet count as independent predictors for both decreased neutrophil and platelet counts following CD19 CAR T-cell infusion. Furthermore, multivariable models including CRS-related cytokines identified associations between higher peak serum concentrations of IL-6 and lower day-28 counts; in contrast, higher serum concentrations of TGF-β were associated with higher counts. Our findings suggest that patient selection and improved CRS management may improve hematopoietic recovery following CD19 CAR T-cell therapy.

Is Chemotherapy Associated with Improved Overall Survival in Patients with Dedifferentiated Chondrosarcoma? A SEER Database Analysis

Clin Orthop Relat Res

2021 Elizabeth Loggers; Matthew Thompson; Lee Cranmer; Teresa Kim; Seth Pollack; Edward Kim; Michael Wagner

BACKGROUND: Dedifferentiated chondrosarcoma is a chondrosarcoma subtype associated with high rates of recurrence and a poor prognosis. Others have proposed treatment of dedifferentiated chondrosarcoma using osteosarcoma protocols, including perioperative chemotherapy. However, the rarity of this condition poses difficulties in undertaking single- institution studies of sufficient sample size. QUESTION/PURPOSE: Is perioperative chemotherapy associated with improved overall survival in patients with dedifferentiated chondrosarcoma? METHODS: We queried the Surveillance, Epidemiology, and End Results (SEER) 1973 to 2016 database for patients with a diagnosis of dedifferentiated chondrosarcoma (n = 308). As dedifferentiated chondrosarcoma was only classified as a distinct entity in SEER starting in 2000, only patients treated in 2000 and later were included. We excluded from our analyses those patients with distant disease at diagnosis, a primary site of disease other than bone or joints, and those who did not receive cancer-directed surgery. These criteria yielded 185 dedifferentiated chondrosarcoma patients for inclusion. We used Kaplan-Meier analyses and Cox proportional hazards models to assess the association of clinical, demographic, and treatment characteristics on overall survival (OS). RESULTS: After controlling for confounding variables, including age, sex, tumor size, stage, grade, location, and radiation treatment status, and after adjusting for missing data, no overall survival benefit was associated with receipt of chemotherapy in patients with dedifferentiated chondrosarcoma (hazard ratio 0.75 [95% confidence interval 0.49 to 1.12]; p = 0.16). CONCLUSION: Chemotherapy treatment of dedifferentiated chondrosarcoma was not associated with improved OS. These results must be viewed cautiously, given the limited granularity of information on chemotherapy treatment, the concerns regarding chemotherapy misclassification in SEER data, and the small sample of patients with dedifferentiated chondrosarcoma, all of which limit the power to detect a difference. Our findings are nevertheless consistent with those of prior reports in which no benefit of chemotherapy could be detected. Lack of clear benefit from perioperative chemotherapy in dedifferentiated chondrosarcoma argues that it should be used only after careful consideration, and ideally in the context of a clinical trial. LEVEL OF EVIDENCE: Level III, therapeutic study.

Hematopoietic cell transplantation after CD19 CAR T cell-induced ALL remission confers leukemia-free survival advantage

Transplant Cell Ther

2021 Qian (Vicky) Wu; Colleen Annesley; Rebecca Gardner; Michael Jensen; Julie Park; Jenna Voutsinas; Marie Bleakley; Ann Dahlberg; Wendy Leisenring; Corinne Summers

BACKGROUND: Consolidative hematopoietic cell transplantation (HCT) after CD19 chimeric antigen receptor (CAR) T cell therapy is frequently performed for patients with refractory/relapsed B cell acute lymphoblastic leukemia (B-ALL). However, there is controversy regarding the role of HCT following remission attainment. OBJECTIVES: We evaluated the effect of consolidative HCT on leukemia-free survival (LFS) in pediatric and young adult subjects following CD19 CAR T cell induced remission. STUDY DESIGN: We evaluated the effect of consolidative HCT on leukemia-free survival (LFS) in pediatric and young adult subjects treated with a 41BB-CD19 CAR T cell product on a Phase 1/2 trial, Pediatric and Young Adult Leukemia Adoptive Therapy (PLAT)-02 (NCT02028455), using a time-dependent Cox proportional hazards statistical model. Fifty of 64 subjects enrolled onto PLAT-02 Phase 1 and early Phase 2 were evaluated, excluding 14 subjects who did not achieve remission, relapsed or died prior to day 63 post-CAR T cell therapy. RESULTS: An improved LFS (P=0.01) was observed in subjects who underwent consolidative HCT after CAR T cell therapy versus watchful waiting. Consolidative HCT improved LFS specifically in subjects who had no prior history of HCT, with a trend towards significance (P=0.09). This benefit was not evident when restricted to the cohort of 34 subjects with a history of a prior HCT (P=0.45). However, for subjects who had CAR T cell functional persistence of 63 days or less, inclusive of those with a history of prior HCT, HCT significantly improved LFS outcomes (P=0.01). CONCLUSIONS: These data support consolidative HCT following CD19 CAR T cell-induced remission for patients with no prior history of HCT or for those with short functional CAR T cell persistence.

Attenuation of apoptotic cell detection triggers thymic regeneration after damage

Cell Rep

2021 Kirsten Cooper; Jarrod Dudakov; Cindy Evandy; David Granadier; Kayla Hopwo; Lorenzo Iovino; Sinéad Kinsella; Colton Smith; Paul deRoos

The thymus, which is the primary site of T cell development, is particularly sensitive to insult but also has a remarkable capacity for repair. However, the mechanisms orchestrating regeneration are poorly understood, and delayed repair is common after cytoreductive therapies. Here, we demonstrate a trigger of thymic regeneration, centered on detecting the loss of dying thymocytes that are abundant during steady-state T cell development. Specifically, apoptotic thymocytes suppressed production of the regenerative factors IL-23 and BMP4 via TAM receptor signaling and activation of the Rho-GTPase Rac1, the intracellular pattern recognition receptor NOD2, and micro-RNA-29c. However, after damage, when profound thymocyte depletion occurs, this TAM-Rac1-NOD2-miR29c pathway is attenuated, increasing production of IL-23 and BMP4. Notably, pharmacological inhibition of Rac1-GTPase enhanced thymic function after acute damage. These findings identify a complex trigger of tissue regeneration and offer a regenerative strategy for restoring immune competence in patients whose thymic function has been compromised.

Humoral immunogenicity of the seasonal influenza vaccine before and after CAR-T-cell therapy: a prospective observational study

J Immunother Cancer

2021 David Maloney; Cameron Turtle; Rebecca Gardner; Mathilda Loeffelholz; Andrea Loes; Jesse Bloom; Damian Green; Jacob Keane-Candib; Justin Taylor; Jim Boonyaratanakornkit; Andrew Cowan; Joshua Hill; Carla Walti; Elizabeth Krantz; Steven Pergam

Recipients of chimeric antigen receptor-modified T (CAR-T) cell therapies for B cell malignancies have profound and prolonged immunodeficiencies and are at risk for serious infections, including respiratory virus infections. Vaccination may be important for infection prevention, but there are limited data on vaccine immunogenicity in this population. We conducted a prospective observational study of the humoral immunogenicity of commercially available 2019-2020 inactivated influenza vaccines in adults immediately prior to or while in durable remission after CD19-, CD20-, or B cell maturation antigen-targeted CAR-T-cell therapy, as well as controls. We tested for antibodies to all four vaccine strains using neutralization and hemagglutination inhibition (HAI) assays. Antibody responses were defined as at least fourfold titer increases from baseline. Seroprotection was defined as a HAI titer ≥40. Enrolled CAR-T-cell recipients were vaccinated 14-29 days prior to (n=5) or 13-57 months following therapy (n=13), and the majority had hypogammaglobulinemia and cellular immunodeficiencies prevaccination. Eight non-immunocompromised adults served as controls. Antibody responses to ≥1 vaccine strain occurred in 2 (40%) individuals before CAR-T-cell therapy and in 4 (31%) individuals vaccinated after CAR-T-cell therapy. An additional 1 (20%) and 6 (46%) individuals had at least twofold increases, respectively. One individual vaccinated prior to CAR-T-cell therapy maintained a response for >3 months following therapy. Across all tested vaccine strains, seroprotection was less frequent in CAR-T-cell recipients than in controls. There was evidence of immunogenicity even among individuals with low immunoglobulin, CD19+ B cell, and CD4+ T-cell counts. These data support consideration for vaccination before and after CAR-T-cell therapy for influenza and other relevant pathogens such as SARS-CoV-2, irrespective of hypogammaglobulinemia or B cell aplasia. However, relatively impaired humoral vaccine immunogenicity indicates the need for additional infection-prevention strategies. Larger studies are needed to refine our understanding of potential correlates of vaccine immunogenicity, and durability of immune responses, in CAR-T-cell therapy recipients.

Autologous Transplant versus Chimeric Antigen Receptor T-cell Therapy for Relapsed DLBCL in Partial Remission


2021 Mazyar Shadman; Cameron Turtle

The relative efficacy of autologous hematopoietic cell transplant (auto-HCT) versus chimeric antigen receptor T-cell (CAR-T) therapy in diffuse large B-cell lymphoma (DLBCL) patients who achieve a partial remission (PR) after salvage chemotherapy is not known. Using the Center for International Blood & Marrow Transplant Research registry database, we identified adult DLBCL patients who received either an auto-HCT (2013-2019) or CAR-T treatment with axicabtagene ciloleucel (2018-2019) while in a PR by CT or PET scan. We compared the clinical outcomes between the two cohorts using univariable and multivariable regression models after adjustment for relevant baseline and clinical factors. In the univariable analysis, the 2-year progression-free survival (52% vs. 42% ; p=0.1) and the rate of 100-day non-relapse mortality (4% vs. 2% ; p=0.3) were not different between the 2 cohorts but consolidation with auto-HCT was associated with a lower rate of relapse/progression (40% vs. 53% ; p=0.05) and a superior overall survival (OS) (69% vs. 47% ; p=0.004) at 2-years. In the multivariable regression analysis, treatment with auto-HCT was associated with a significantly lower risk of relapse/progression rate (HR=1.49; p=0.01) and a superior OS (HR=1.63; p=0.008). In patients with DLBCL in a PR after salvage therapy, treatment with auto-HCT was associated with a lower incidence of relapse and a superior OS compared with CAR-T. These data support the role of auto-HCT as the standard-of-care in transplant-eligible patients with relapsed DLBCL in PR after salvage therapy.