Publications by authors named "Saad S Kenderian"

44 Publications

CRISPR Takes the Front Seat in CART-Cell Development.

BioDrugs 2021 Feb 27. Epub 2021 Feb 27.

T Cell Engineering, Mayo Clinic, Rochester, MN, USA.

Chimeric antigen receptor T (CART)-cell immunotherapies have opened a door in the development of specialized gene therapies for hematological and solid cancers. Impressive response rates in pivotal trials led to the FDA approval of CART-cell therapy for certain hematological malignancies. However, autologous CART products are costly and time-intensive to manufacture, and most patients experience disease relapse within 1 year of CART administration. Additionally, CART-cell efficacy in solid tumors is extremely limited. CART-cell therapy is also associated with serious toxicities. Manufacturing difficulties, intrinsic T-cell defects, CART exhaustion, and treatment-associated toxicities are some of the current barriers to widespread adoption of CART-cell therapy. Genome editing tools such as CRISPR/Cas systems have demonstrated efficacy in further engineering CART cells to overcome these limitations. In this review, we will summarize the current approaches that use CRISPR to facilitate off-the-shelf CART products, increase CART-cell efficacy, and minimize CART-associated toxicities.
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http://dx.doi.org/10.1007/s40259-021-00473-yDOI Listing
February 2021

CART Cell Toxicities: New Insight into Mechanisms and Management.

Clin Hematol Int 2020 Dec 23;2(4):149-155. Epub 2020 Nov 23.

T Cell Engineering, Mayo Clinic, Rochester, MN, USA.

T cells genetically engineered with chimeric antigen receptors (CART) have become a potent class of cancer immunotherapeutics. Numerous clinical trials of CART cells have revealed remarkable remission rates in patients with relapsed or refractory hematologic malignancies. Despite recent clinical success, CART cell therapy has also led to significant morbidity and occasional mortality from associated toxicities. Cytokine release syndrome (CRS) and Immune effector cell-associated neurotoxicity syndrome (ICANS) present barriers to the extensive use of CART cell therapy in the clinic. CRS can lead to fever, hypoxia, hypotension, coagulopathies, and multiorgan failure, and ICANS can result in cognitive dysfunction, seizures, and cerebral edema. The mechanisms of CRS and ICANS are becoming clearer, but many aspects remain unknown. Disease type and burden, peak serum CART cell levels, CART cell dose, CAR structure, elevated pro-inflammatory cytokines, and activated myeloid and endothelial cells all contribute to CART cell toxicity. Current guidelines for the management of toxicities associated with CART cell therapy vary between clinics, but are typically comprised of supportive care and treatment with corticosteroids or tocilizumab, depending on the severity of the symptoms. Acquiring a deeper understanding of CART cell toxicities and developing new management and prevention strategies are ongoing. In this review, we present findings in the mechanisms and management of CART cell toxicities.
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http://dx.doi.org/10.2991/chi.k.201108.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7785104PMC
December 2020

Leukemic extracellular vesicles induce chimeric antigen receptor T cell dysfunction in chronic lymphocytic leukemia.

Mol Ther 2021 Jan 1. Epub 2021 Jan 1.

T Cell Engineering, Mayo Clinic, Rochester, MN, USA; Division of Hematology, Mayo Clinic, Rochester, MN 55905, USA; Mayo Clinic Graduate School of Biomedical Sciences, Rochester, MN, USA; Department of Molecular Medicine, Mayo Clinic, Rochester, MN, USA; Department of Immunology, Mayo Clinic, Rochester, MN, USA. Electronic address:

Chimeric antigen receptor (CAR) T cell therapy has yielded unprecedented outcomes in some patients with hematological malignancies; however, inhibition by the tumor microenvironment has prevented the broader success of CART cell therapy. We used chronic lymphocytic leukemia (CLL) as a model to investigate the interactions between the tumor microenvironment and CART cells. CLL is characterized by an immunosuppressive microenvironment, an abundance of systemic extracellular vesicles (EVs), and a relatively lower durable response rate to CART cell therapy. In this study, we characterized plasma EVs from untreated CLL patients and identified their leukemic cell origin. CLL-derived EVs were able to induce a state of CART cell dysfunction characterized by phenotypical, functional, and transcriptional changes of exhaustion. We demonstrate that, specifically, PD-L1 CLL-derived EVs induce CART cell exhaustion. In conclusion, we identify an important mechanism of CART cell exhaustion induced by EVs from CLL patients.
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http://dx.doi.org/10.1016/j.ymthe.2020.12.033DOI Listing
January 2021

GM-CSF Neutralization With Lenzilumab in Severe COVID-19 Pneumonia: A Case-Cohort Study.

Mayo Clin Proc 2020 11 3;95(11):2382-2394. Epub 2020 Sep 3.

Division of Infectious Diseases, Mayo Clinic, Rochester, MN; Department of Molecular Medicine, Mayo Clinic, Rochester, MN.

Objective: To assess the efficacy and safety of lenzilumab in patients with severe coronavirus disease 2019 (COVID-19) pneumonia.

Methods: Hospitalized patients with COVID-19 pneumonia and risk factors for poor outcomes were treated with lenzilumab 600 mg intravenously for three doses through an emergency single-use investigational new drug application. Patient characteristics, clinical and laboratory outcomes, and adverse events were recorded. We also identified a cohort of patients matched to the lenzilumab patients for age, sex, and disease severity. Study dates were March 13, 2020, to June 18, 2020. All patients were followed through hospital discharge or death.

Results: Twelve patients were treated with lenzilumab; 27 patients comprised the matched control cohort (untreated). Clinical improvement, defined as improvement of at least 2 points on the 8-point ordinal clinical endpoints scale, was observed in 11 of 12 (91.7%) patients treated with lenzilumab and 22 of 27 (81.5%) untreated patients. The time to clinical improvement was significantly shorter for the lenzilumab-treated group compared with the untreated cohort with a median of 5 days versus 11 days (P=.006). Similarly, the proportion of patients with acute respiratory distress syndrome (oxygen saturation/fraction of inspired oxygen<315 mm Hg) was significantly reduced over time when treated with lenzilumab compared with untreated (P<.001). Significant improvement in inflammatory markers (C-reactive protein and interleukin 6) and markers of disease severity (absolute lymphocyte count) were observed in patients who received lenzilumab, but not in untreated patients. Cytokine analysis showed a reduction in inflammatory myeloid cells 2 days after lenzilumab treatment. There were no treatment-emergent adverse events attributable to lenzilumab.

Conclusion: In high-risk COVID-19 patients with severe pneumonia, granulocyte-macrophage colony-stimulating factor neutralization with lenzilumab was safe and associated with faster improvement in clinical outcomes, including oxygenation, and greater reductions in inflammatory markers compared with a matched control cohort of patients hospitalized with severe COVID-19 pneumonia. A randomized, placebo-controlled clinical trial to validate these findings is ongoing (NCT04351152).
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http://dx.doi.org/10.1016/j.mayocp.2020.08.038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7470718PMC
November 2020

Anti-CD19 chimeric antigen receptor T-cell therapy in acute lymphocytic leukaemia: a systematic review and meta-analysis.

Lancet Haematol 2020 Nov;7(11):e816-e826

Division of Haematology, Mayo Clinic, Rochester, MN, USA; Department of Immunology, Mayo Clinic, Rochester, MN, USA; T-Cell Engineering, Mayo Clinic, Rochester, MN, USA; Department of Molecular Medicine, Mayo Clinic, Rochester, MN, USA. Electronic address:

Background: Anti-CD19 chimeric antigen receptor (CAR) T-cell therapy has shown remarkable activity in patients with refractory or relapsed acute lymphocytic leukaemia. Various anti-CD19 CAR T-cell constructs have been trialled and responses vary widely among different studies. We aimed to systematically analyse the outcomes of patients with acute lymphocytic leukaemia treated with anti-CD19 CAR T cells and identify factors associated with differences in outcomes.

Methods: We did a systematic review and meta-analysis of published and unpublished clinical trials that reported data on the outcomes of adult or paediatric patients that were treated with anti-CD19 CAR T cells for relapsed or refractory B-cell acute lymphocytic leukaemia, reported between Jan 1, 2012, and April 14, 2020. Studies with two patients or fewer were excluded and summary data were extracted from the reports. The primary outcome was the number of patients who had complete remission at any time after anti-CD19 CAR T-cell infusion. This study is not registered in PROSPERO.

Findings: From 1160 studies, we identified 40 potentially appropriate studies, 35 (88%) of which met the eligibility criteria and were included in the final analysis (n=953 patients). The pooled complete remission was 80% (95% CI 75·5-84·8) and heterogeneity between studies was moderate (I=56·96%). In the prespecified subgroup analyses, 195 (75% [95% CI 66·9-82·9, I=35·22%]) of 263 patients in adult studies and 242 (81% [72·9-87·2, I=54·45%]) of 346 patients in paediatric studies achieved complete remission, p=0·24. The pooled complete remission did not significantly differ with anti-CD19 CAR T-cell construct type or single-chain variable fragment clone, but was higher with autologous T-cell origin (727 [83%, 78·5-86·5, I=44·34%] of 901 patients), compared with allogeneic T-cell origin (29 [55%, 30·6-79·0, I=62·64%] of 52 patients; p=0·018). 242 (26% [95% CI 18·5-34·1]) of 854 patients developed grade 3 or worse cytokine release syndrome and 97 (12% [6·6-19·2]) of 532 developed grade 3 or worse neurotoxicity. There was no difference in the proportion of patients who achieved complete remission or who had cytokine release syndrome or neurotoxicity between different anti-CD19 CAR T-cell constructs. The risk of bias was assessed as low in 17 studies and moderate in 18 studies.

Interpretation: The high response rates after anti-CD19 CAR T-cell therapy can be used to guide the use of therapy in patients with relapsed or refractory acute lymphocytic leukaemia. Comparison studies are required to further determine differences in efficacy between different anti-CD19 CAR T-cell constructs in the setting of relapsed or refractory acute lymphocytic leukaemia.

Funding: National Cancer Institute, National Comprehensive Cancer Network, Mayo Clinic K2R Research Pipeline, and Mayo Clinic Center for Individualized Medicine.
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http://dx.doi.org/10.1016/S2352-3026(20)30277-5DOI Listing
November 2020

A Concise Review of Neurologic Complications Associated with Chimeric Antigen Receptor T-cell Immunotherapy.

Neurol Clin 2020 11 12;38(4):953-963. Epub 2020 Sep 12.

T Cell Engineering, Mayo Clinic, 200 First Street Southwest, Rochester, MN 55905, USA; Division of Hematology, Mayo Clinic, 200 First Street Southwest, Rochester, MN 55905, USA; Department of Molecular Medicine, Mayo Clinic, 200 First Street Southwest, Rochester, MN 55905, USA; Department of Immunology, Mayo Clinic, 200 First Street Southwest, Rochester, MN 55905, USA. Electronic address:

Chimeric antigen receptor-engineered T (CAR-T) cell immunotherapy has been successful in treating many types of hematological malignancies. CAR-T therapy, however, has been associated with toxicities, including cytokine release syndrome (CRS) as well as immune effector cell-associated neurotoxicity syndrome (ICANS). ICANS presentation is variable, largely reversible, and manifests with encephalopathy and focal neurologic deficits. Treatment strategies largely are supportive. ICANS pathophysiology likely is related to that of CRS. Preclinical studies and clinical experience have shed light on the driving forces of ICANS and have yielded new strategies to mitigate ICANS occurrence.
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http://dx.doi.org/10.1016/j.ncl.2020.08.001DOI Listing
November 2020

Neurotoxicity and Cytokine Release Syndrome After Chimeric Antigen Receptor T Cell Therapy: Insights Into Mechanisms and Novel Therapies.

Front Immunol 2020 28;11:1973. Epub 2020 Aug 28.

T Cell Engineering, Mayo Clinic, Rochester, MN, United States.

Chimeric antigen receptor T (CART) cell immunotherapy has been remarkably successful in treating certain relapsed/refractory hematological cancers. However, CART cell therapy is also associated with toxicities which present an obstacle to its wider adoption as a mainstay for cancer treatment. The primary toxicities following CART cell administration are cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). New insights into the mechanisms of these toxicities have spurred novel treatment options. In this review, we summarize the available literature on the clinical manifestations, mechanisms, and treatments of CART-associated CRS and ICANS.
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http://dx.doi.org/10.3389/fimmu.2020.01973DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7485001PMC
August 2020

Disease Flare During Temporary Interruption of Ibrutinib Therapy in Patients with Chronic Lymphocytic Leukemia.

Oncologist 2020 11 20;25(11):974-980. Epub 2020 Sep 20.

Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, Minnesota, USA.

Background: Approximately 25% of patients with chronic lymphocytic leukemia (CLL) experience a flare of disease following ibrutinib discontinuation. A critical question is whether this phenomenon may also occur when ibrutinib is temporarily held. This study aimed to determine the frequency and characteristics of disease flares in this setting and assess risk factors and clinical outcomes.

Materials And Methods: We identified all patients with CLL seen at Mayo Clinic between October 2012 and March 2019 who received ibrutinib. Temporary interruptions in treatment and associated clinical findings were ascertained.

Results: Among the 372 patients identified, 143 (38%) had at least one temporary interruption (median 1 hold, range 1-7 holds) in treatment. The median duration of interruption was 8 days (range 1-59 days) and the most common indication was periprocedural. Among the 143 patients with ≥1 hold, an associated disease flare was seen in 35 (25%) patients: mild (constitutional symptoms only) in 21 patients and severe (constitutional symptoms with exam/radiographic findings or laboratory changes) in 14 patients. Disease flare resolved with resuming ibrutinib in all patients. Predictive factors of disease flare included progressive disease at time of hold and ≥ 24 months of ibrutinib exposure. The occurrence of disease flare with an ibrutinib hold was associated with shorter event-free survival (hazard ratio 2.3; 95% confidence interval 1.3-4.1; p = .007) but not overall survival.

Conclusion: Temporary interruptions in ibrutinib treatment of patients with CLL are common, and one quarter of patients who held ibrutinib in this study experienced a disease flare. Resolution with resuming ibrutinib underscores the importance of awareness of this phenomenon for optimal management.

Implications For Practice: Ibrutinib is a very effective treatment for chronic lymphocytic leukemia (CLL) but needs to be taken continuously. Side effects, such as increased bleeding risk with procedures, require temporary interruptions in this continuous treatment. Rapid CLL progression following ibrutinib discontinuation has been increasingly recognized. This study demonstrates that similar flares in disease signs or symptoms may occur during ibrutinib holds as well. Importantly, management with restarting ibrutinib led to quick clinical improvement. Awareness of this phenomenon among clinicians is critical to avoid associated patient morbidity and premature cessation of effective treatment with ibrutinib if the flare is misidentified as true progression of disease.
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http://dx.doi.org/10.1634/theoncologist.2020-0388DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7648348PMC
November 2020

CRISPR Taking the Front Seat in Immunotherapy.

J Cell Immunol 2020 ;2(4):143-148

Department of Molecular Medicine, Mayo Clinic, Rochester, MN, USA.

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http://dx.doi.org/10.33696/immunology.2.032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7406201PMC
January 2020

Characteristics of late transplant-associated thrombotic microangiopathy in patients who underwent allogeneic hematopoietic stem cell transplantation.

Am J Hematol 2020 Jul 2. Epub 2020 Jul 2.

Division of Hematology, Mayo Clinic, Rochester, Minnesota.

Transplant-associated thrombotic microangiopathy (TA-TMA) has a wide range of presentations after hematopoietic stem-cell transplantation (HSCT). We retrospectively studied the risk factors and outcomes of patients with early (≤day 100) and late (>day 100) TA-TMA. Among the 1451 HSCT recipients, early TA-TMA occurred in 45 (3.1%) patients at a median of 27 (3-91) days, and late TA-TMA in 39 (2.7%) patients at a median of 303 (122-2595) days. Patients with early TA-TMA were more likely to have high blood calcineurin-inhibitor levels (P < .001) and acute graph-vs-host disease (GVHD, P < .001), while late TMA patients were more likely to have chronic GVHD (P < .001). The estimated median overall survival after onset of TMA for the entire cohort was 6 months. The estimated median overall survival was not reached in patients with an improvement of TMA vs 2 months in patients with no improvement (P < .001). In the early TMA group, older age (for every 10 years, HR 1.40; 95% CI 1.00-1.94; P = .049) and bacterial infection (HR 2.42; 95% CI 0.98-6.00; P = .056) were positively associated with mortality. Switching to MMF treatment (HR 0.40; 95% CI 0.16-0.99; P = .047) and improvement of TMA (HR 0.08; 95% CI 0.03-0.25; P < .001) were negatively associated with mortality in the multivariate analysis. In the late TMA group, the improvement of TMA was the only independent predictor associated with a lower risk of death (HR 0.05; 95% CI 0.02-0.19; P < .001). Mortality rates in both early and late TMA remain unacceptably high. Future studies are needed for early diagnosis, trigger identifications, and use of targeted treatments.
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http://dx.doi.org/10.1002/ajh.25922DOI Listing
July 2020

First Clinical Use of Lenzilumab to Neutralize GM-CSF in Patients with Severe COVID-19 Pneumonia.

medRxiv 2020 Jun 14. Epub 2020 Jun 14.

Background: In COVID-19, high levels of granulocyte macrophage-colony stimulating factor (GM-CSF) and inflammatory myeloid cells correlate with disease severity, cytokine storm, and respiratory failure. With this rationale, we used lenzilumab, an anti-human GM-CSF monoclonal antibody, to treat patients with severe COVID-19 pneumonia.

Methods: Hospitalized patients with COVID-19 pneumonia and risk factors for poor outcomes were treated with lenzilumab 600 mg intravenously for three doses through an emergency single-use IND application. Patient characteristics, clinical and laboratory outcomes, and adverse events were recorded. All patients receiving lenzilumab through May 1, 2020 were included in this report.

Results: Twelve patients were treated with lenzilumab. Clinical improvement was observed in 11 out of 12 (92%), with a median time to discharge of 5 days. There was a significant improvement in oxygenation: The proportion of patients with SpO2/FiO2 < 315 at the end of observation was 8% vs. compared to 67% at baseline (p=0.00015). A significant improvement in mean CRP and IL-6 values on day 3 following lenzilumab administration was also observed (137.3 mg/L vs 51.2 mg/L, p = 0.040; 26.8 pg/mL vs 16.1 pg/mL, p = 0.035; respectively). Cytokine analysis showed a reduction in inflammatory myeloid cells two days after lenzilumab treatment. There were no treatment-emergent adverse events attributable to lenzilumab, and no mortality in this cohort of patients with severe COVID-19 pneumonia.

Conclusions: In high-risk COVID-19 patients with severe pneumonia, GM-CSF neutralization with lenzilumab was safe and associated with improved clinical outcomes, oxygen requirement, and cytokine storm.
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http://dx.doi.org/10.1101/2020.06.08.20125369DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7310641PMC
June 2020

Atrial fibrillation in patients with chronic lymphocytic leukemia (CLL) treated with ibrutinib: risk prediction, management, and clinical outcomes.

Ann Hematol 2021 Jan 1;100(1):143-155. Epub 2020 Jun 1.

Division of Hematology, Department of Medicine, Mayo Clinic, 200 First St SW, Rochester, MN, 55905, USA.

Background: Ibrutinib therapy is associated with an increased risk of atrial fibrillation (AF) in chronic lymphocytic leukemia (CLL). Risk assessment tools and outcomes of AF in these patients are not well described.

Methods: We performed a retrospective review of patients with CLL treated with ibrutinib at Mayo Clinic between October 2012 and November 2018.

Results: Two hundred ninety-eight patients were identified with a median time on ibrutinib of 19 months (range 0.23-69.7 months). Fifty-one patients developed treatment-emergent AF; the risk of treatment-emergent AF at 6 months, 1 year, and 2 years was 9%, 12%, and 16%, respectively. The following were associated with an increased risk of treatment-emergent AF on multivariable analyses: past history of AF (hazard ratio [HR] 3.5, p = 0.0072) and heart failure (HR 3.4, p = 0.0028). Most patients are able to continue ibrutinib therapy (dose reduced in 43%). Development of treatment-emergent AF was associated with shorter event-free survival (EFS; HR 2.0, p = 0.02) and shorter overall survival (OS; HR 3.2, p = 0.001), after adjusting for age, prior treatment status, TP53 disruption, heart failure, valvular disease, and past history of AF.

Conclusions: Patient comorbidities, rather than CLL-related factors, predict risk of treatment-emergent AF in patients treated with ibrutinib. Although the vast majority of patients with treatment-emergent AF are able to continue ibrutinib (with dose reduction in 43%), treatment-emergent AF appears to be associated with worse outcomes, independent of other adverse prognostic factors.
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http://dx.doi.org/10.1007/s00277-020-04094-3DOI Listing
January 2021

Incidence and risk of tumor lysis syndrome in patients with relapsed chronic lymphocytic leukemia (CLL) treated with venetoclax in routine clinical practice.

Leuk Lymphoma 2020 10 25;61(10):2383-2388. Epub 2020 May 25.

Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, MN, USA.

The risk of TLS in patients with relapsed CLL treated outside of clinical trials is not well described. Using the Mayo Clinic CLL Database, 48 patients treated with venetoclax for relapsed CLL in routine practice were identified; chart review determined baseline risk for TLS and laboratory abnormalities during venetoclax ramp-up. Overall, 6 (13%) patients developed laboratory TLS, 3 of whom demonstrated clinical TLS. The majority of patients who developed TLS were stratified as low or medium risk by the package insert. Of the 42 patients who did not meet Howard criteria for TLS, isolated hyperphosphatemia occurred in 19 patients (45%), hyperkalemia in 13 patients (31%), hyperuricemia in 2 patients (5%), and hypocalcemia in 1 patient (2%). In routine practice, the incidence of TLS appears higher than reported in clinical trials (3-6%). Half of patients who did not meet criteria for TLS developed clinically significant electrolyte abnormalities that required medical intervention.
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http://dx.doi.org/10.1080/10428194.2020.1768384DOI Listing
October 2020

Human chimeric antigen receptor macrophages for cancer immunotherapy.

Nat Biotechnol 2020 08 23;38(8):947-953. Epub 2020 Mar 23.

Center for Cellular Immunotherapies, University of Pennsylvania School of Medicine, Philadelphia, PA, USA.

Chimeric antigen receptor (CAR) T cell therapy has shown promise in hematologic malignancies, but its application to solid tumors has been challenging. Given the unique effector functions of macrophages and their capacity to penetrate tumors, we genetically engineered human macrophages with CARs to direct their phagocytic activity against tumors. We found that a chimeric adenoviral vector overcame the inherent resistance of primary human macrophages to genetic manipulation and imparted a sustained pro-inflammatory (M1) phenotype. CAR macrophages (CAR-Ms) demonstrated antigen-specific phagocytosis and tumor clearance in vitro. In two solid tumor xenograft mouse models, a single infusion of human CAR-Ms decreased tumor burden and prolonged overall survival. Characterization of CAR-M activity showed that CAR-Ms expressed pro-inflammatory cytokines and chemokines, converted bystander M2 macrophages to M1, upregulated antigen presentation machinery, recruited and presented antigen to T cells and resisted the effects of immunosuppressive cytokines. In humanized mouse models, CAR-Ms were further shown to induce a pro-inflammatory tumor microenvironment and boost anti-tumor T cell activity.
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http://dx.doi.org/10.1038/s41587-020-0462-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7883632PMC
August 2020

CAR T-cell therapy for the management of refractory/relapsed high-grade B-cell lymphoma: a practical overview.

Bone Marrow Transplant 2020 08 18;55(8):1525-1532. Epub 2020 Apr 18.

The Chaim Sheba Medical Center, Tel-Hashomer, Affiliated with the Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel.

The goal of this review is to firstly address the concept of chimeric antigen receptor T-cell (CAR T-cell) therapy and where it fits in the evolving landscape of the management of patients with refractory/relapsed diffuse large B-cell lymphoma. The recognition of the indications for CAR T-cell therapy for patients with aggressive B-cell lymphoma will be discussed, including a review of the algorithms and selection criteria for CAR T-cell therapy and finally, the role of bridging therapy and the timing of CAR T-cell therapy in augmenting chances of a successful outcome.
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http://dx.doi.org/10.1038/s41409-020-0892-7DOI Listing
August 2020

A Graduate-Level Interdisciplinary Curriculum in CAR-T Cell Therapy.

Mayo Clin Proc Innov Qual Outcomes 2020 Apr 16;4(2):203-210. Epub 2020 Mar 16.

Department of Immunology, Mayo Clinic, Rochester, MN.

Objective: To evaluate the impact of a novel interdisciplinary graduate-level course in chimeric antigenic receptor-T cell therapy on students' knowledge and interests in translational science.

Materials/participants And Methods: The course ran November 12 to 16, 2018. Students were surveyed before and after the course. The survey included questions regarding background, self-perceived knowledge/confidence in skills, and interests/predicted behaviors. Students were assigned to work in collaborative interdisciplinary teams to develop a research proposal.

Results: A total of 25 students taking the course for graduate-level credit were surveyed. Of these, all 25 (100%) completed the surveys. Students came from variable backgrounds and were at different stages of graduate training. After completion of the course, there was a statistically significant increase in self-perceived knowledge of immunotherapy (mean score of 3.6 postcourse vs 2.6 precourse, on a 5-point Likert scale; <.001), knowledge of the bench to clinic translational process (3.7 postcourse vs 3.0 precourse; <.001), confidence in critical reading skills (4.3 postcourse vs 4.0 precourse; =.008), confidence in immunotherapy-focused grant writing skills (3.6 postcourse vs 2.8 precourse; <.001), and interest in working in interdisciplinary teams (4.8 postcourse vs 4.6 precourse; =.02).

Conclusion: The structure of this innovative and comprehensive course serves as a platform for educational courses in interdisciplinary translational research and helps trainees build knowledge and interest in the fields of chimeric antigenic receptor-T cells, regenerative sciences, and immunotherapy.
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http://dx.doi.org/10.1016/j.mayocpiqo.2019.12.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7140137PMC
April 2020

The impact of dose modification and temporary interruption of ibrutinib on outcomes of chronic lymphocytic leukemia patients in routine clinical practice.

Cancer Med 2020 05 18;9(10):3390-3399. Epub 2020 Mar 18.

Division of Hematology, Stanford University School of Medicine, Palo Alto, CA, USA.

To study the impact of dose modification and temporary interruption of ibrutinib in routine clinical practice, we conducted a retrospective study of consecutive CLL patients treated with ibrutinib outside the context of a clinical trial at Mayo Clinic, (Rochester, MN) from 11/2013 to 12/2017. Of 209 patients, 131 (74%) had unmutated IGHV, 38 (20%) had TP53 disruption, and 47 (22%) were previously untreated. A total of 87/209 (42%) patients started reduced dose ibrutinib (<420 mg daily; n = 43, physician preference; n = 33, concomitant medications; and n = 11, other). During 281 person-years of treatment, 91/209 patients had temporary dose interruption (54%, nonhematologic toxicity; 29%, surgical procedures; 10%, hematologic toxicity; and 7%, other). After a median follow-up of 24 months, the estimated median event-free survival (EFS) was 36 months, and median overall survival (OS) was not reached. On multivariable analyses, temporary ibrutinib interruption (hazard ratio [HR]: 2.37, P = .006) and TP53 disruption at ibrutinib initiation (HR: 1.81, P = .048) were associated with shorter EFS, whereas only TP53 disruption (HR: 2.38, P = .015) was associated with shorter OS. Initial ibrutinib dose and dose modification during therapy did not appear to impact EFS or OS. These findings illustrate the challenges associated with continuous oral therapy with ibrutinib in patients with CLL.
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http://dx.doi.org/10.1002/cam4.2998DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7221301PMC
May 2020

Myeloid cell and cytokine interactions with chimeric antigen receptor-T-cell therapy: implication for future therapies.

Curr Opin Hematol 2020 01;27(1):41-48

Department of Immunology.

Purpose Of Review: Chimeric antigen receptor (CAR)-T-cell therapy is a revolutionary tool in the treatment of cancer. CAR-T cells exhibit their effector functions through the recognition of their specific antigens on tumor cells and recruitment of other immune cells. However, this therapy is limited by the development of severe toxicities and modest antitumor activity in solid tumors. The host and tumor microenvironment interactions with CAR-T cells play an important role in orchestrating CAR-T-cell functions. Specifically, myeloid lineage cells and their cytokines critically influence the behavior of CAR-T cells. Here, we review the specific effects of myeloid cell interactions with CAR-T cells, their impact on CAR-T-cell response and toxicities, and potential efforts to modulate myeloid cell effects to enhance CAR-T-cell therapy efficacy and reduce toxicities.

Recent Findings: Independent studies and correlative science from clinical trials indicate that inhibitory myeloid cells and cytokines contribute to the development of CAR-T-cell-associated toxicities and impairment of their effector functions.

Summary: These findings illuminate a novel way to reduce CAR-T-cell-associated toxicities and enhance their efficacy through the modulation of myeloid lineage cells and inhibitory cytokines.
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http://dx.doi.org/10.1097/MOH.0000000000000559DOI Listing
January 2020

Using CRISPR/Cas9 to Knock Out GM-CSF in CAR-T Cells.

J Vis Exp 2019 07 22(149). Epub 2019 Jul 22.

Department of Immunology, Mayo Clinic; Division of Hematology, Mayo Clinic;

Chimeric antigen receptor T (CAR-T) cell therapy is a cutting edge and potentially revolutionary new treatment option for cancer. However, there are significant limitations to its widespread use in the treatment of cancer. These limitations include the development of unique toxicities such as cytokine release syndrome (CRS) and neurotoxicity (NT) and limited expansion, effector functions, and anti-tumor activity in solid tumors. One strategy to enhance CAR-T efficacy and/or control toxicities of CAR-T cells is to edit the genome of the CAR-T cells themselves during CAR-T cell manufacturing. Here, we describe the use of CRISPR/Cas9 gene editing in CAR-T cells via transduction with a lentiviral construct containing a guide RNA to granulocyte macrophage colony-stimulating factor (GM-CSF) and Cas9. As an example, we describe CRISPR/Cas9 mediated knockout of GM-CSF. We have shown that these GM-CSF CAR-T cells effectively produce less GM-CSF while maintaining critical T cell function and result in enhanced anti-tumor activity in vivo compared to wild type CAR-T cells.
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http://dx.doi.org/10.3791/59629DOI Listing
July 2019

Clinical characteristics and outcomes of Richter transformation: experience of 204 patients from a single center.

Haematologica 2020 03 13;105(3):765-773. Epub 2019 Jun 13.

Division of Hematology, Mayo Clinic, Rochester, MN

The natural history, prognostication and optimal treatment of Richter transformation developed from chronic lymphocytic leukemia (CLL) are not well defined. We report the clinical characteristics and outcomes of a large series of biopsy-confirmed Richter transformation (diffuse large B-cell lymphoma or high grade B-cell lymphoma, n=204) cases diagnosed from 1993 to 2018. After a median follow up of 67.0 months, the median overall survival (OS) was 12.0 months. Patients who received no prior treatment for CLL had significantly better OS (median 46.3 7.8 months; <0.001). Patients with elevated lactate dehydrogenase (median 6.2 39.9 months; <0.0001) or disruption (median 8.3 12.8 months; =0.046) had worse OS than those without. Immunoglobulin heavy chain variable region gene mutation, cell of origin, Myc/Bcl-2 double expression and double-/triple-hit status were not associated with OS. In multivariable Cox regression, elevated lactate dehydrogenase [Hazard ratio (HR) 2.3, 95% Confidence Interval (CI): 1.3-4.1; =0.01], prior CLL treatment (HR 2.0, 95%CI: 1.2-3.5; =0.01), and older age (HR 1.03, 95%CI: 1.01-1.05; =0.01) were associated with worse OS. Twenty-four (12%) patients underwent stem cell transplant (20 autologous and 4 allogeneic), and had a median post-transplant survival of 55.4 months. In conclusion, the overall outcome of Richter transformation is poor. Richter transformation developed in patients with untreated CLL has significantly better survival. Stem cell transplant may benefit select patients.
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http://dx.doi.org/10.3324/haematol.2019.224121DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7049354PMC
March 2020

Management of cytokine release syndrome: an update on emerging antigen-specific T cell engaging immunotherapies.

Immunotherapy 2019 07 4;11(10):851-857. Epub 2019 Jun 4.

Department of Immunology, Mayo Clinic, 200 First St SW, Rochester, MN 55905, USA.

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http://dx.doi.org/10.2217/imt-2019-0074DOI Listing
July 2019

Rapid disease progression following discontinuation of ibrutinib in patients with chronic lymphocytic leukemia treated in routine clinical practice.

Leuk Lymphoma 2019 11 24;60(11):2712-2719. Epub 2019 Apr 24.

Department of Medicine, Division of Hematology, Mayo Clinic, Rochester, MN, USA.

We identified all patients with chronic lymphocytic leukemia at Mayo Clinic treated with ibrutinib outside the context of a clinical trial; timing and reasons for discontinuation were ascertained, as were symptoms, exam and radiographic findings, and laboratory changes following discontinuation. Of 202 patients who received ibrutinib, 52 discontinued therapy (estimated 1- and 2-year risk of discontinuation 18% and 28%, respectively). The most common reasons for discontinuation were toxicity (56%) and progression of disease (32%, including Richter's transformation in 15%). Rapid progression of disease within 4 weeks after discontinuation was observed in 9/36 (25%) patients with adequate records for review, mostly in those stopping ibrutinib for disease progression ( = 8) rather than toxicity ( = 1). This was evident by sudden worsening of disease-related symptoms ( = 9), exam/radiographic changes ( = 7), and laboratory changes ( = 8). An estimated one in every three patients discontinued ibrutinib by 2 years, with 25% developing rapid disease progression afterwards.
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http://dx.doi.org/10.1080/10428194.2019.1602268DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6813846PMC
November 2019

CAR T Cell Immunotherapy in Human and Veterinary Oncology: Changing the Odds Against Hematological Malignancies.

AAPS J 2019 04 8;21(3):50. Epub 2019 Apr 8.

Department of Medicine, Mayo Clinic Division of Hematology, Rochester, Minnesota, 55905, USA.

The advent of the genome editing era brings forth the promise of adoptive cell transfer using engineered chimeric antigen receptor (CAR) T cells for targeted cancer therapy. CAR T cell immunotherapy is probably one of the most encouraging developments for the treatment of hematological malignancies. In 2017, two CAR T cell therapies were approved by the US Food and Drug Administration: one for the treatment of pediatric acute lymphoblastic leukemia (ALL) and the other for adult patients with advanced lymphomas. However, despite significant progress in the area, CAR T cell therapy is still in its early days and faces significant challenges, including the complexity and costs associated with the technology. B cell lymphoma is the most common hematopoietic cancer in dogs, with an incidence approaching 0.1% and a total of 20-100 cases per 100,000 individuals. It is a widely accepted naturally occurring model for human non-Hodgkin's lymphoma. Current treatment is with combination chemotherapy protocols, which prolong life for less than a year in canines and are associated with severe dose-limiting side effects, such as gastrointestinal and bone marrow toxicity. To date, one canine study generated CAR T cells by transfection of mRNA for CAR domain expression. While this was shown to provide a transient anti-tumor activity, results were modest, indicating that stable, genomic integration of CAR modules is required in order to achieve lasting therapeutic benefit. This commentary summarizes the current state of knowledge on CAR T cell immunotherapy in human medicine and its potential applications in animal health, while discussing the potential of the canine model as a translational system for immuno-oncology research.
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http://dx.doi.org/10.1208/s12248-019-0322-1DOI Listing
April 2019

IGH translocations in chronic lymphocytic leukemia: Clinicopathologic features and clinical outcomes.

Am J Hematol 2019 03 8;94(3):338-345. Epub 2019 Jan 8.

Division of Hematology, Mayo Clinic, Rochester, Minnesota.

The prevalence, clinicopathologic correlates, and outcomes of previously untreated chronic lymphocytic leukemia (CLL) patients with IGH-BCL2 and IGH-BCL3 translocations are not well known. Using the Mayo Clinic CLL database, we identified patients seen between March 1, 2002 and September 30, 2016 who had FISH testing performed within 3 years of CLL diagnosis. The prognostic profile, time to first therapy (TTT), and overall survival (OS) of patients with IGH-BCL2 and IGH-BCL3 translocation were compared to patients without these abnormalities (non-IGH group). Of 1684 patients who met the inclusion criteria, 38 (2.2%) had IGH-BCL2, and 16 (0.9%) had IGH-BCL3 translocation at diagnosis. Patients with IGH-BCL3 translocation were more likely to have high and very-high CLL-International Prognostic Index, compared to patients with IGH-BCL2 translocation and the non-IGH group. The 5-year probability of requiring therapy was significantly higher for IGH-BCL3 compared to IGH-BCL2 and non-IGH groups (84% vs 33% vs 29%, respectively, P < 0.0001). The 5-year OS was significantly shorter for IGH-BCL3 compared to IGH-BCL2 and non-IGH groups (45% vs 89% vs 86%, respectively, P < 0.0001). On multivariable analyses, IGH-BCL3 translocation was associated with a shorter TTT (hazard ratio [HR] = 2.7; P = 0.005) and shorter OS (HR = 5.5; P < 0.0001); IGH-BCL2 translocation did not impact TTT and OS. In conclusion, approximately 3% of all newly diagnosed CLL patients have either an IGH-BCL2 or IGH-BCL3 translocation. Patients with IGH-BCL3 translocations have a distinct prognostic profile and outcome. These results support the inclusion of an IGH probe during the routine evaluation of FISH abnormalities in newly diagnosed CLL.
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http://dx.doi.org/10.1002/ajh.25385DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6625355PMC
March 2019

GM-CSF inhibition reduces cytokine release syndrome and neuroinflammation but enhances CAR-T cell function in xenografts.

Blood 2019 02 21;133(7):697-709. Epub 2018 Nov 21.

Department of Immunology.

Chimeric antigen receptor T (CAR-T) cell therapy is a new pillar in cancer therapeutics; however, its application is limited by the associated toxicities. These include cytokine release syndrome (CRS) and neurotoxicity. Although the IL-6R antagonist tocilizumab is approved for treatment of CRS, there is no approved treatment of neurotoxicity associated with CD19-targeted CAR-T (CART19) cell therapy. Recent data suggest that monocytes and macrophages contribute to the development of CRS and neurotoxicity after CAR-T cell therapy. Therefore, we investigated neutralizing granulocyte-macrophage colony-stimulating factor (GM-CSF) as a potential strategy to manage CART19 cell-associated toxicities. In this study, we show that GM-CSF neutralization with lenzilumab does not inhibit CART19 cell function in vitro or in vivo. Moreover, CART19 cell proliferation was enhanced and durable control of leukemic disease was maintained better in patient-derived xenografts after GM-CSF neutralization with lenzilumab. In a patient acute lymphoblastic leukemia xenograft model of CRS and neuroinflammation (NI), GM-CSF neutralization resulted in a reduction of myeloid and T cell infiltration in the central nervous system and a significant reduction in NI and prevention of CRS. Finally, we generated GM-CSF-deficient CART19 cells through CRISPR/Cas9 disruption of GM-CSF during CAR-T cell manufacturing. These GM-CSF CAR-T cells maintained normal functions and had enhanced antitumor activity in vivo, as well as improved overall survival, compared with CART19 cells. Together, these studies illuminate a novel approach to abrogate NI and CRS through GM-CSF neutralization, which may potentially enhance CAR-T cell function. Phase 2 studies with lenzilumab in combination with CART19 cell therapy are planned.
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http://dx.doi.org/10.1182/blood-2018-10-881722DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6376281PMC
February 2019

Chimeric Antigen Receptor T-Cells: Successful Translation of the First Cell and Gene Therapy From Bench to Bedside.

Clin Transl Sci 2018 11 22;11(6):537-539. Epub 2018 Sep 22.

Center for Clinical and Translational Science, Mayo Clinic Graduate School of Biomedical Sciences, Rochester, Minnesota, USA.

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http://dx.doi.org/10.1111/cts.12586DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6226113PMC
November 2018