scholarly journals Safety and Response of Incorporating CD19 Chimeric Antigen Receptor T Cell Therapy in Typical Salvage Regimens for Children and Young Adults with Acute Lymphoblastic Leukemia

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 684-684 ◽  
Author(s):  
Daniel W. Lee ◽  
Maryalice Stetler-Stevenson ◽  
Constance M. Yuan ◽  
Terry J. Fry ◽  
Nirali N Shah ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Disease Burden ◽  
Low Dose ◽  
High Dose ◽  
T Cell Therapy ◽  
High Burden ◽  
Car T Cells ◽  
Car T ◽  
Preparative Regimen

CD19 chimeric antigen receptor (CAR) T cells have shown significant promise in multiple early phase trials including our own (Lancet 385:517-28). We manufacture CAR T cells containing CD28 and CD3z domains in 7 days using a retroviral platform. Several challenges remain to its widespread use: 1) reduction in the incidence of grade 4 cytokine release syndrome (CRS) and 2) incorporation with standard salvage regimens. Here, we update our experience with 39 patients. In the first 21 patients we defined the maximally tolerated dose as 1x106 CAR T cells/kg, grade 4 CRS occurred in 16%, and noted that severity of CRS correlated with disease burden. We stratified the current cohort (n=18) by disease burden. Subjects 1-21 and subsequent patients with low burden disease (Arm 1: isolated CNS disease or <25% marrow blasts) received a low dose preparative regimen of fludarabine (25 mg/m2/day Days-4 to -2) and cyclophosphamide (900 mg/m2 Day-2). Those with high burden disease (Arm 2: ³25% marrow blasts, circulating blasts or lymphomatous disease) received a high dose regimen to reduce tumor burden prior to cell infusion in an attempt to decrease severity of CRS. Arm 2 regimens were individualized based on prior therapies and risk from comorbidities. FLAG (n=6), ifosfamide/etoposide per AALL0031 (IE; n=2) and high dose fludarabine (30 mg/m2/day Days -6 to -3) with cyclophosphamide (1200 mg/m2/day Days -4 and -3) (HD flu/cy; n=3) were used. All products in the second cohort met cell dose though contaminating monocytes tended to inhibit maximal growth and transduction (see companion abstract by Stroncek). All patients received 1x106 CAR T cells/kg. Using grading criteria and an algorithm for early intervention to prevent grade 4 CRS (Blood 124:188-95) no grade 3 and only 1 grade 4 (5.6%) CRS occurred. Having significant comorbidities, Pt 34 was electively intubated for airway protection, did not require vasopressors, and rapidly recovered after tocilizumab and steroids. A brief seizure occurred, though he had a history of seizures. None others in the current cohort had neurotoxicity. Using intent to treat analysis, the complete response (CR) rate was 59% overall and 61% in ALL. 13/16 (81%) low burden and 10/22 (46%) high burden ALL patients had a CR across both cohorts. Low burden patients treated on either cohort had similar CR rate of 8/10 (80%) and 5/6 (83%). Although not statistically significant and underpowered, 7/11 (64%) high burden patients treated with low dose flu/cy had a CR while 3/11 (27%) had a CR with high dose regimens. Specifically, 3/6 (50%) receiving FLAG achieved MRD-CR while none receiving IE or HD flu/cy responded. 8/8 with primary refractory ALL had MRD-CR regardless of disease burden or preparative regimen raising the prospect that T cell fitness in these patients was superior to others. Of the 20 patients achieving an MRD-CR, the median leukemia free survival (LFS) is 17.7 months with 45.5% probability of LFS beginning at 18 months. Only 3 did not have a subsequent hematopoietic stem cell transplant as their referring oncologist determined the risk of such was unacceptable. Two relapsed with CD19-leukemia at 3 and 5 months, while 1 remains in CR with detectable CAR T cells at 5 months. Reliance on multiple infusions of cells is problematic as 0/5 CD19+ patients receiving a second dose responded. Preclinical models have demonstrated that T cell exhaustion has a role in limiting the efficacy of CAR T cells. We evaluated CAR products and the T cells used to generate them for phenotypic markers of exhaustion and will present data evaluating the relationship between these and response. Our results demonstrate that CD19 CAR T cell therapy is safe and effective with aggressive supportive care and use of an early intervention algorithm to prevent severe CRS and provides a potential for cure in primary refractory ALL. Table. Patient Characteristics, Response, and Toxicity Pt Age/ Sex/Risk # Relapses Arm/Prep Regimen(if Arm 2) Marrow Blasts Response CRS Grade Pre-Therapy Post CAR 22 17M 3 1 20 0 MRD- 2 23 13M 2 2 IE 99 98 SD 0 24 12M MLL 2 1 8.5 3 CR 1 25 25F 1 2 FLAG 95 0 MRD- 2 26 4M DS 2 2 IE (60%) 89 NA PD 0 27 8F 2 2 FLAG 77 69 SD 0 28 4M 2 2 FLAG (60%) 99 99 PD 0 29 12M PR 1 0.15 0 MRD- 1 30 15M Ph+ CNS2 3 1 0.08 0 MRD- 1 31 22M 3 2 FLAG 97 99 SD 0 32 15M CNS2 3 2 FLAG 0.04 + Lymphoma 0 MRD- 2 33 6M PR 1 0.15 0 MRD- 0 34 14M DS 3 2 Arm 1 Flu/Cy 90 0 MRD- 4 35 25M 2 2 HD Flu/Cy 30 87 PD 2 36 6M 2 1 1.5 91 PD 0 37 4F MLL 1 2 HD Flu/Cy 90 99 SD 0 38 7M 1 2 HD Flu/Cy 99 99 SD 1 Disclosures Off Label Use: Off-label use of tocilizumab will be discussed in managing cytokine release syndrome.. Rosenberg:Kite Pharma: Other: CRADA between Surgery Branch-NCI and Kite Pharma. Mackall:Juno: Patents & Royalties: CD22-CAR.

Updated results from ZUMA-3, a phase 1/2 study of KTE-C19 chimeric antigen receptor (CAR) T cell therapy, in adults with high-burden relapsed/refractory acute lymphoblastic leukemia (R/R ALL).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 3024-3024 ◽  
Author(s):  
Bijal D. Shah ◽  
William G. Wierda ◽  
Gary J. Schiller ◽  
Michael Russell Bishop ◽  
Januario E. Castro ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Therapy ◽  
Disease Burden ◽  
Phase 1 ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T

3024 Background: Promising results have been observed with KTE-C19, an anti-CD19 CAR T cell therapy, in refractory aggressive NHL in the ZUMA-1 trial (Blood 2016;128:LBA-6). We present here updated results from the ZUMA-3 phase 1 trial of KTE-C19 in adult patients (pts) with R/R ALL. Methods: Adult (≥18 y) pts with R/R ALL (Ph+ eligible), ≥25% bone marrow (BM) blasts, adequate organ function and ECOG status 0-1 received 1 or 2×106 CAR T cells/kg after conditioning with cyclophosphamide + fludarabine. Phase 1 primary endpoint is incidence of dose-limiting toxicity (DLT). Secondary endpoints include efficacy outcomes and biomarker associations. Results: As of Nov 1, 2016, 11 pts were enrolled; 10 received KTE-C19. One pt had a serious adverse event (SAE) prior to dosing and was not treated. KTE-C19 was successfully manufactured in all pts across a broad range of baseline absolute lymphocyte counts in 6 days in a centralized facility, with an approximate 2-week turnaround time. Pts were 60% men with 1-4 prior lines of therapy and high disease burden (median, 70% BM blasts). No pt (0/3) experienced a DLT at the 2×106 dose. Phase 1 was expanded to 6 pts at the same dose; 1 grade (Gr) 5 AE (multiorgan failure due to cytokine release syndrome [CRS]) was observed. Subsequent pts (4) received 1×106 CAR T cells/kg. Overall, the most common Gr≥3 AEs were cytopenias (80%), febrile neutropenia (50%), pyrexia (40%), and transaminitis (40%). Gr≥3 CRS and neurologic events (NEs) were reported in 20% and 40% of pts, respectively. Cerebral edema was not observed. All CRS (except Gr5) and 5 of 6 NEs (1 Gr3 ongoing at cut-off) resolved. Of the 8 efficacy evaluable pts, 6 achieved an MRD-negative (MRD–) complete response (CR, or CR + partial or incomplete hematopoietic recovery). Updated results will include additional pt follow-up and biomarker data. Conclusions: No DLTs were observed with KTE-C19 in adult pts with high BM disease burden; one pt had G5 CRS after the DLT cohort. Manufacturing was successful in all pts; most pts achieved an MRD– CR. Based on these results, ZUMA-3 continues to enroll pts with additional measures implemented to further enhance safety. Clinical trial information: NCT02614066.

scholarly journals Adult Patients with ALL Treated with CD62L+ T Naïve/Memory-Enriched T Cells Expressing a CD19-CAR Mediate Potent Antitumor Activity with a Low Toxicity Profile

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4016-4016 ◽  
Author(s):  
Samer K. Khaled ◽  
Suzette Blanchard ◽  
Xiuli Wang ◽  
Jamie Wagner ◽  
Araceli Naranjo ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Research Funding ◽  
Disease Burden ◽  
Phase 1 ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Car T ◽  
Manufacturing Platform ◽  
Grade 3

Abstract Introduction: Treatment of adults with relapsed/refractory (R/R) B-ALL using CD19-targeted chimeric antigen receptor (CAR) T cells has achieved remarkable remission rates, both in pediatric and adult populations. There are multiple CAR constructs and T cell manufacturing platforms in use, and both aspects of the therapy may impact efficacy and toxicity. Park et al. report that 83% of adult patients (pts) achieve complete response (CR) to their CD19 CAR T cells with a CD28 costimulatory domain (NEJM; 3785: 449), using an unselected peripheral blood (PBMC) manufacturing platform. Unfortunately, therapy-associated toxicities in adult and pediatric ALL pts are problematic, with grade 3/4 cytokine release syndrome (CRS) ranging from 26-49 % and neurotoxicity 18-42%. Here we report preliminary data from one arm of a phase 1 clinical trial (NCT02146924) in adult pts with R/R B-ALL testing a memory-enriched T cell starting population engineered to express a CD19-specific, CD28-costimulatory CAR (CD19:28z-CAR). All pts achieved CR or CRi with a low incidence of severe cytokine release syndrome (CRS) and neurotoxicity. Unique to this study is our Tn/mem-enriched manufacturing platform, a naïve/memory T cell-enriched T cell product that is lentivirally transduced to express our CD19:28z-CAR. The manufacturing process starts with patient PBMC, depletes the CD14+ monocytes and CD25+ Tregs, and selects for CD62L+ T cells. The resultant T cell population for CAR transduction includes both the central memory and stem cell memory populations along with naïve T cells. Preclinical studies in mice had suggested that using a more uniform T cell product with a less-differentiated T cell phenotype improved antitumor activity. This Tn/mem manufacturing platform is the same as our Tcm-derived platform (Blood;127:2980) except that CD45RA depletion was omitted. Patients and Methods: This phase I study used the activity constrained for toxicity (ACT) design, an extension of the toxicity equivalence range (TEQR) design of Blanchard and Longmate (Contemp Clin Trials; 32:114), that dose escalates based on lack of activity, while constraining the dose for toxicity. The primary objectives of this study were to test the safety and activity of Tn/mem-enriched CD19:28z CAR T cells, and to determine the phase 2 recommended dose. The primary endpoints were toxicity and disease response. Sixteen pts were consented and received a lymphodepleting regimen (LDR) of 1.5-3 gm/m2 cyclophosphamide over 2-3 days and 25-30 mg/m2 fludarabine for 3 days. Three pts received LDR, but did not receive T cells due to infection or lack of CD19+ disease. Patients received a flat dose of 200 million (M) CD19:28z-CAR T cells: 11 autologous and 2 allogeneic donor products. Of the 13 that received 200 M CAR+ T cells, 2 pts were deemed ineligible for dose escalation / disease response evaluation, as 1 received <80% of the prescribed dose (100 M) and the other had CD19-negative extramedullary disease. The median age of the 13 CAR T cell treated pts was 33 years (24-72). All pts had active bone marrow (BM) disease at the time of LDR: 8 pts (62%) had high disease burden (15-91% BM blasts) and 5 had low disease burden (</= 5% BM blasts). Patients were heavily pretreated, with a median of 5 (2-6), prior regimens. Six pts received prior allogeneic transplant (HSCT), 9 had prior blinatumomab, and 1 had prior CD19 CAR T cells. Results: Toxicity: Table 1 describes the major toxicities of the 13 CAR-treated pts, stratified based on disease burden. There were no DLTs, and T-cell therapy attributed (>/=possibly) toxicities were typically mild and reversible. Eight pts had grade 2 CRS, and 2 had grade 3 CRS. Three pts had grade 2 neurotoxicity and 2 had grade 3. Response: Eleven pts were evaluable for response, with best response of 4 CRs (MRD- by flow) and 7 CRi (6 MRD-, 1 not tested). Median response duration at last contact or HSCT start was 81 days (39-286); 8 pts proceeded to HSCT (in CR or CRi) at a median of 69 days post-CAR infusion (39-103). Conclusions: Our ongoing phase 1 trial demonstrates a 100% response rate to Tn/mem-enriched CD19:28z-CAR T cell therapy in adults with relapsed/refractory (R/R) B-ALL. Although the numbers are small, the unanimous response, combined with a tolerable and reversible toxicity profile in pts with both low and high disease burden is remarkable and suggests promise for this Tn/mem manufacturing platform for CD19 and other CAR targets. Disclosures Khaled: Juno: Other: Travel Funding; Daiichi: Consultancy; Alexion: Consultancy, Speakers Bureau. Wang:Mustang Therapeutics: Other: Licensing Agreement, Patents & Royalties, Research Funding. Brown:Mustang Therapeutics: Consultancy, Other: Licensing Agreement, Patents & Royalties, Research Funding. Forman:Mustang Therapeutics: Other: Licensing Agreement, Patents & Royalties, Research Funding.

Durable long-term survival of adult patients with relapsed B-ALL after CD19 CAR (19-28z) T-cell therapy.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 7008-7008 ◽  
Author(s):  
Jae Hong Park ◽  
Isabelle Riviere ◽  
Xiuyan Wang ◽  
Brigitte Senechal ◽  
Yongzeng Wang ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Disease Burden ◽  
Adult Patients ◽  
Term Survival ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T

7008 Background: CD19-specific chimeric antigen receptor (CAR) T cells have demonstrated high initial responses in patients with relapsed B-ALL. However, clinical characteristics associated with the durability of response remain undefined. Herein, we report the results from analysis of our phase I clinical trial of 19-28z CAR T cells in adult patients with relapsed B-ALL (NCT01044069) with a focus to identify those patients who optimally benefit from 19-28z CAR T cell therapy with durable long-term survival and reduced toxicities. Methods: Adults with relapsed B-ALL were infused with autologous T cells expressing the 19-28z CAR following conditioning chemotherapy. Disease burden was assessed by bone marrow biopsy immediately prior to T cell infusion; patients with < 5% blasts were classified as minimal residual disease (MRD) cohort vs. patients ≥5% blasts as morphologic disease cohort. Response assessment occurred at 4 weeks. Median follow-up duration was 18 months (range, 0.2-57.3). Results: 51 adults received 19-28z CAR T cells; 20 in the MRD and 31 in the morphologic cohort. Complete remission (CR) rates were comparable (95% and 77%, respectively). However, median event-free and overall survivals widely diverged among the 42 patients who achieved MRD-negative CR: not reached (NR) (95% confidence interval [CI]: 4.2-NR) vs. 6.3 months (95% CI, 4.8-9.0) (p = 0.0005), and NR (95% CI, 15.3-NR) vs. 17 months (95% CI, 8.5 – 36.2) (p = 0.0189), in the MRD and morphologic cohorts, respectively. Subsequent allogeneic HSCT in either cohort did not improve survival (p = 0.8). MRD cohort patients developed substantially less severe cytokine release syndrome (CRS) and neurotoxicity, both correlating with peak CAR T cell expansion (p = 0.0326 and p = 0.0001, respectively). Conclusions: Despite comparable initial CR rates regardless of pre-treatment disease burden, durability of 19-28z CAR T cell mediated remissions and survival in adult patients with relapsed B-ALL positively correlated to a low disease burden and do not appear to be enhanced by allogeneic transplant. Our findings strongly support the early incorporation of CD19 CAR therapy before morphologic relapse in B-ALL. Clinical trial information: NCT01044069.

Clinical responses and pharmacokinetics of fully human BCMA targeting CAR T-cell therapy in relapsed/refractory multiple myeloma.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 8013-8013 ◽  
Author(s):  
chunrui li ◽  
Jianfeng Zhou ◽  
Jue Wang ◽  
Guang Hu ◽  
Aihua Du ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
T Cells ◽  
T Cell ◽  
Rapid Response ◽  
High Dose ◽  
T Cell Therapy ◽  
Refractory Multiple Myeloma ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T

8013 Background: Previous studies indicate patients with relapsed/refractory multiple myeloma (RRMM) who receive high-dose BCMA-targeting CAR-T cells may achieve better remission but have worse adverse events. Moreover, once the disease progresses again, the re-infusion of CAR-T cells is not effective. To solve this dilemma, we have developed a novel BCMA-targeting CAR-T (CT103A) with a lentiviral vector containing a CAR structure with a fully human scFv, CD8a hinger and transmembrane, 4-1BB co-stimulatory and CD3z activation domains. Methods: ChiCTR1800018137 is a single-center and single-arm trial of CT103A in patients with RRMM. The primary objectives are to characterize the safety and tolerability in patients with R/R MM. The secondary objectives include evaluation of anti-myeloma activity, cytokines, CAR-T cell persistence, and pharmacokinetics. Between September 21, 2018, and January 21, 2019, nine patients (including 3 patients having relapsed after being given a murine BCMA CAR-T) received CT103A in 3+3 dose-escalation trial (three doses at 1, 3, 6 ×106/kg) after a conditioning chemotherapy regimen of cyclophosphamide and fludarabine. All Patients had received a median of 4 prior lines (range 3 - 5) of MM therapy. Results: At the time of the February 4, 2019 data analysis, the overall response rate was 100% (Table), and all patients had a rapid response within 14 days, with 67% (2/3) reaching CR/sCR at the lowest dose. The pharmacokinetics of CT103A were assessed by a digital polymerase chain reaction. Robust expansions were seen even at the lowest dosage level. In addition, Cmax and AUC0-28 reached levels comparable to reported CD19 CAR-T. In the first two dose groups, the grade of cytokine release syndrome (CRS) was 0 - 2. In the 6 ×106 /kg dose group, DLT had been observed in one patient. Conclusions: Data from this early-stage clinical study showed the unparalleled safety and efficacy of CT103A. Major AEs were transient, manageable, and reversible. three patients who relapsed the murine BCMA CAR-T were treated with CT103A, two patients achieved CR, and one patient achieved VGPR. 100% ORR and a rapid response within 2 weeks, suggests CT103A could be developed as a competitive therapeutic to treat patients with RRMM. Treatment Response (Case 1,5 and 7 are patients who relapsed the murine BCMA CAR-T). Clinical trial information: ChiCTR1800018137. [Table: see text]

scholarly journals Anti-CD19 CAR T Cells Administered after Low-Dose Chemotherapy Can Induce Remissions of Chemotherapy-Refractory Diffuse Large B-Cell Lymphoma

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 550-550 ◽  
Author(s):  
James N Kochenderfer ◽  
Robert Somerville ◽  
Lily Lu ◽  
Alex Iwamoto ◽  
James C Yang ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cell ◽  
Low Dose ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
High Dose ◽  
Car T Cells ◽  
Car T ◽  
Low Dose Chemotherapy

Abstract We have treated a total of 30 patients with autologous T cells genetically modified to express a chimeric antigen receptor (CAR) targeting the B-cell antigen CD19; 22 of 27 evaluable patients obtained either complete remissions (CR) or partial remissions (PR). Ten patients remain in ongoing CRs of 1 to 37 months duration. The CAR was encoded by a gammaretroviral vector and included the variable regions of an anti-CD19 antibody along with CD28 and CD3-zeta moieties. The first 21 patients treated on this protocol have been reported (Kochenderfer et al. Blood 2010, Blood 2012, and Journal of Clinical Oncology 2014). To enhance the activity of the transferred CAR T cells, T-cell infusions in the previously reported patients were preceded by a chemotherapy regimen of high-dose cyclophosphamide (60-120 mg/kg) plus fludarabine. In an attempt to reduce the overall toxicity of our anti-CD19 CAR treatment protocol, we substantially reduced the doses of chemotherapy administered before CAR T-cell infusions. This abstract communicates results from 9 patients with B-cell lymphoma who received a single infusion of 1x106 anti-CD19-CAR-expressing T cells/kg bodyweight preceded by a low-dose chemotherapy regimen consisting of cyclophosphamide 300 mg/m2 and fludarabine 30 mg/m2 (Table). Each chemotherapy agent was administered daily for 3 days. Eight of the 9 treated patients had DLBCL (diffuse large B-cell lymphoma) that was refractory to chemotherapy (chemo-refractory) or that had relapsed less than 1 year after autologous stem cell transplantation (ASCT). Both of these clinical situations carry a grim prognosis, with median overall survivals of only a few months. Despite the very poor prognoses of our patients, one patient with DLBCL obtained a CR and 4 DLBCL patients obtained PRs. In some patients, PRs included resolution of large lymphoma masses. Compared to our previous experience with anti-CD19 CAR T cells preceded by high-dose chemotherapy, toxicity was reduced when CAR T cells were infused after low-dose chemotherapy. None of the 9 patients treated with low-dose chemotherapy and CAR T cells required vasopressor drugs or mechanical ventilation, although some patients did have short-term neurological toxicity. Cytopenias were mild with a mean of only 1.4 days of blood neutrophils<500/microliter. Blood anti-CD19 CAR T-cell levels were assessed in 6 patients with a quantitative PCR assay; we detected CAR+ cells in the blood of all 6 patients. The mean peak absolute number of blood CAR+ T cells was 73 cells/microliter. Six months after infusion, persisting CAR+ T cells were detected in a lymphoma-involved lymph node by flow cytometry. These results demonstrate that anti-CD19 CAR T cells administered after low-dose chemotherapy have significant activity against chemo-refractory DLBCL and could potentially become a standard treatment for aggressive lymphoma. Table Patient Age/Gender Malignancy Number of Prior Therapies Clinical Situation Response (Duration in Months) 1 66/M DLBCL 3 Post ASCT relapse PR (7) 2* 63/F DLBCL 2 Chemo-refractory PR (7+) 3 63/M FL 7 Not chemo-refractory PR (6+) 4* 22/M DLBCL 6 Chemo-refractory Progression 5 65/M DLBCL 4 Post ASCT relapse PR (5+) 6 47/M DLBCL 2 Chemo-refractory PR (1) 7 28/M DLBCL 7 Chemo-refractory Progression 8 62/M DLBCL 7 Post ASCT relapse CR (1+) 9 54/M DLBCL 3 Chemo-refractory Progression * Compassionate exemption was obtained from regulatory agencies to enroll these patients because their poor performance status precluded standard enrollment; M = male; F = female; FL = follicular lymphoma; + indicates ongoing response Disclosures Rosenberg: Kite Pharma: Membership on an entity's Board of Directors or advisory committees, Research Funding.

scholarly journals Anti-Mesothelin CAR T cell therapy for malignant mesothelioma

2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Laura Castelletti ◽  
Dannel Yeo ◽  
Nico van Zandwijk ◽  
John E. J. Rasko
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Therapy ◽  
Malignant Mesothelioma ◽  
Oncolytic Viruses ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T

AbstractMalignant mesothelioma (MM) is a treatment-resistant tumor originating in the mesothelial lining of the pleura or the abdominal cavity with very limited treatment options. More effective therapeutic approaches are urgently needed to improve the poor prognosis of MM patients. Chimeric Antigen Receptor (CAR) T cell therapy has emerged as a novel potential treatment for this incurable solid tumor. The tumor-associated antigen mesothelin (MSLN) is an attractive target for cell therapy in MM, as this antigen is expressed at high levels in the diseased pleura or peritoneum in the majority of MM patients and not (or very modestly) present in healthy tissues. Clinical trials using anti-MSLN CAR T cells in MM have shown that this potential therapeutic is relatively safe. However, efficacy remains modest, likely due to the MM tumor microenvironment (TME), which creates strong immunosuppressive conditions and thus reduces anti-MSLN CAR T cell tumor infiltration, efficacy and persistence. Various approaches to overcome these challenges are reviewed here. They include local (intratumoral) delivery of anti-MSLN CAR T cells, improved CAR design and co-stimulation, and measures to avoid T cell exhaustion. Combination therapies with checkpoint inhibitors as well as oncolytic viruses are also discussed. Preclinical studies have confirmed that increased efficacy of anti-MSLN CAR T cells is within reach and offer hope that this form of cellular immunotherapy may soon improve the prognosis of MM patients.

scholarly journals Spatio-temporal biodistribution of 89Zr-oxine labeled huLym-1-A-BB3z-CAR T-cells by PET imaging in a preclinical tumor model

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Naomi S. Sta Maria ◽  
Leslie A. Khawli ◽  
Vyshnavi Pachipulusu ◽  
Sharon W. Lin ◽  
Long Zheng ◽  
...  
Keyword(s):  
T Cells ◽  
Real Time ◽  
Pet Imaging ◽  
Dose Group ◽  
Low Dose ◽  
High Dose ◽  
Car T Cells ◽  
Nsg Mice ◽  
Car T

AbstractQuantitative in vivo monitoring of cell biodistribution offers assessment of treatment efficacy in real-time and can provide guidance for further optimization of chimeric antigen receptor (CAR) modified cell therapy. We evaluated the utility of a non-invasive, serial 89Zr-oxine PET imaging to assess optimal dosing for huLym-1-A-BB3z-CAR T-cell directed to Lym-1-positive Raji lymphoma xenograft in NOD Scid-IL2Rgammanull (NSG) mice. In vitro experiments showed no detrimental effects in cell health and function following 89Zr-oxine labeling. In vivo experiments employed simultaneous PET/MRI of Raji-bearing NSG mice on day 0 (3 h), 1, 2, and 5 after intravenous administration of low (1.87 ± 0.04 × 106 cells), middle (7.14 ± 0.45 × 106 cells), or high (16.83 ± 0.41 × 106 cells) cell dose. Biodistribution (%ID/g) in regions of interests defined over T1-weighted MRI, such as blood, bone, brain, liver, lungs, spleen, and tumor, were analyzed from PET images. Escalating doses of CAR T-cells resulted in dose-dependent %ID/g biodistributions in all regions. Middle and High dose groups showed significantly higher tumor %ID/g compared to Low dose group on day 2. Tumor-to-blood ratios showed the enhanced extravascular tumor uptake by day 2 in the Low dose group, while the Middle dose showed significant tumor accumulation starting on day 1 up to day 5. From these data obtained over time, it is apparent that intravenously administered CAR T-cells become trapped in the lung for 3–5 h and then migrate to the liver and spleen for up to 2–3 days. This surprising biodistribution data may be responsible for the inactivation of these cells before targeting solid tumors. Ex vivo biodistributions confirmed in vivo PET-derived biodistributions. According to these studies, we conclude that in vivo serial PET imaging with 89Zr-oxine labeled CAR T-cells provides real-time monitoring of biodistributions crucial for interpreting efficacy and guiding treatment in patient care.

scholarly journals Metabolic and Mitochondrial Functioning in Chimeric Antigen Receptor (CAR)—T Cells

Cancers ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 1229
Author(s):  
Ali Hosseini Rad S. M. ◽  
Joshua Colin Halpin ◽  
Mojtaba Mollaei ◽  
Samuel W. J. Smith Bell ◽  
Nattiya Hirankarn ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Therapy ◽  
Chimeric Antigen Receptor ◽  
Metabolic State ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T

Chimeric antigen receptor (CAR) T-cell therapy has revolutionized adoptive cell therapy with impressive therapeutic outcomes of >80% complete remission (CR) rates in some haematological malignancies. Despite this, CAR T cell therapy for the treatment of solid tumours has invariably been unsuccessful in the clinic. Immunosuppressive factors and metabolic stresses in the tumour microenvironment (TME) result in the dysfunction and exhaustion of CAR T cells. A growing body of evidence demonstrates the importance of the mitochondrial and metabolic state of CAR T cells prior to infusion into patients. The different T cell subtypes utilise distinct metabolic pathways to fulfil their energy demands associated with their function. The reprogramming of CAR T cell metabolism is a viable approach to manufacture CAR T cells with superior antitumour functions and increased longevity, whilst also facilitating their adaptation to the nutrient restricted TME. This review discusses the mitochondrial and metabolic state of T cells, and describes the potential of the latest metabolic interventions to maximise CAR T cell efficacy for solid tumours.

98 ATA3271: an armored, next-generation off-the-shelf, allogeneic, mesothelin-CAR T cell therapy for solid tumors

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A109-A109
Author(s):  
Jiangyue Liu ◽  
Xianhui Chen ◽  
Jason Karlen ◽  
Alfonso Brito ◽  
Tiffany Jheng ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Next Generation ◽  
Phase 3 ◽  
T Cell Therapy ◽  
Cell Therapies ◽  
Car T Cells ◽  
Car T

BackgroundMesothelin (MSLN) is a glycosylphosphatidylinositol (GPI)-anchored membrane protein with high expression levels in an array of malignancies including mesothelioma, ovaria, non-small cell lung cancer, and pancreatic cancers and is an attractive target antigen for immune-based therapies. Early clinical evaluation of autologous MSLN-targeted chimeric antigen receptor (CAR)-T cell therapies for malignant pleural mesothelioma has shown promising acceptable safety1 and have recently evolved with incorporation of next-generation CAR co-stimulatory domains and armoring with intrinsic checkpoint inhibition via expression of a PD-1 dominant negative receptor (PD1DNR).2 Despite the promise that MSLN CAR-T therapies hold, manufacturing and commercial challenges using an autologous approach may prove difficult for widespread application. EBV T cells represent a unique, non-gene edited approach toward an off-the-shelf, allogeneic T cell platform. EBV-specific T cells are currently being evaluated in phase 3 trials [NCT03394365] and, to-date, have demonstrated a favorable safety profile including limited risks for GvHD and cytokine release syndrome.3 4 Clinical proof-of-principle studies for CAR transduced allogeneic EBV T cell therapies have also been associated with acceptable safety and durable response in association with CD19 targeting.5 Here we describe the first preclinical evaluation of ATA3271, a next-generation allogeneic CAR EBV T cell therapy targeting MSLN and incorporating PD1DNR, designed for the treatment of solid tumor indications.MethodsWe generated allogeneic MSLN CAR+ EBV T cells (ATA3271) using retroviral transduction of EBV T cells. ATA3271 includes a novel 1XX CAR signaling domain, previously associated with improved signaling and decreased CAR-mediated exhaustion. It is also armored with PD1DNR to provide intrinsic checkpoint blockade and is designed to retain functional persistence.ResultsIn this study, we characterized ATA3271 both in vitro and in vivo. ATA3271 show stable and proportional CAR and PD1DNR expression. Functional studies show potent antitumor activity of ATA3271 against MSLN-expressing cell lines, including PD-L1-high expressors. In an orthotopic mouse model of pleural mesothelioma, ATA3271 demonstrates potent antitumor activity and significant survival benefit (100% survival exceeding 50 days vs. 25 day median for control), without evident toxicities. ATA3271 maintains persistence and retains central memory phenotype in vivo through end-of-study. Additionally, ATA3271 retains endogenous EBV TCR function and reduced allotoxicity in the context of HLA mismatched targets. ConclusionsOverall, ATA3271 shows potent anti-tumor activity without evidence of allotoxicity, both in vitro and in vivo, suggesting that allogeneic MSLN-CAR-engineered EBV T cells are a promising approach for the treatment of MSLN-positive cancers and warrant further clinical investigation.ReferencesAdusumilli PS, Zauderer MG, Rusch VW, et al. Abstract CT036: A phase I clinical trial of malignant pleural disease treated with regionally delivered autologous mesothelin-targeted CAR T cells: Safety and efficacy. Cancer Research 2019;79:CT036-CT036.Kiesgen S, Linot C, Quach HT, et al. Abstract LB-378: Regional delivery of clinical-grade mesothelin-targeted CAR T cells with cell-intrinsic PD-1 checkpoint blockade: Translation to a phase I trial. Cancer Research 2020;80:LB-378-LB-378.Prockop S, Doubrovina E, Suser S, et al. Off-the-shelf EBV-specific T cell immunotherapy for rituximab-refractory EBV-associated lymphoma following transplantation. J Clin Invest 2020;130:733–747.Prockop S, Hiremath M, Ye W, et al. A Multicenter, Open Label, Phase 3 Study of Tabelecleucel for Solid Organ Transplant Subjects with Epstein-Barr Virus-Driven Post-Transplant Lymphoproliferative Disease (EBV+PTLD) after Failure of Rituximab or Rituximab and Chemotherapy. Blood 2019; 134: 5326–5326.Curran KJ, Sauter CS, Kernan NA, et al. Durable remission following ‘Off-the-Shelf’ chimeric antigen receptor (CAR) T-Cells in patients with relapse/refractory (R/R) B-Cell malignancies. Biology of Blood and Marrow Transplantation 2020;26:S89.

scholarly journals Engineering Next-Generation CAR-T Cells for Better Toxicity Management

2020 ◽  
Vol 21 (22) ◽  
pp. 8620
Author(s):  
Alain E. Andrea ◽  
Andrada Chiron ◽  
Stéphanie Bessoles ◽  
Salima Hacein-Bey-Abina
Keyword(s):  
T Cells ◽  
T Cell ◽  
Antigen Receptors ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T ◽  
Safety Strategies ◽  
Life Threatening ◽  
Preclinical And Clinical Studies

Immunoadoptive therapy with genetically modified T lymphocytes expressing chimeric antigen receptors (CARs) has revolutionized the treatment of patients with hematologic cancers. Although clinical outcomes in B-cell malignancies are impressive, researchers are seeking to enhance the activity, persistence, and also safety of CAR-T cell therapy—notably with a view to mitigating potentially serious or even life-threatening adverse events like on-target/off-tumor toxicity and (in particular) cytokine release syndrome. A variety of safety strategies have been developed by replacing or adding various components (such as OFF- and ON-switch CARs) or by combining multi-antigen-targeting OR-, AND- and NOT-gate CAR-T cells. This research has laid the foundations for a whole new generation of therapeutic CAR-T cells. Here, we review the most promising CAR-T cell safety strategies and the corresponding preclinical and clinical studies.

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