Peripheral and tumor immune correlates in patients with advanced melanoma treated with combination nivolumab (anti-PD-1, BMS-936558, ONO-4538) and ipilimumab.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 3003-3003 ◽  
Author(s):  
Margaret K. Callahan ◽  
Christine E. Horak ◽  
Michael A. Curran ◽  
Travis Hollman ◽  
David A. Schaer ◽  
...  
Keyword(s):  
T Cells ◽  
Combination Therapy ◽  
Objective Response ◽  
Predictive Biomarkers ◽  
Tumor Burden ◽  
T Cell Subsets ◽  
Phase Iii ◽  
Tumor Cell Membrane ◽  
Phenotypic Changes ◽  
Immune Correlates

3003^ Background: Nivolumab and ipilimumab are fully human monoclonal antibodies that block the immune checkpoint receptors PD-1 and CTLA-4, respectively. In a multi-cohort, phase I study of nivolumab/ipilimumab combination therapy in melanoma patients (pts), objective response rates up to 47% were observed (NCT01024231). Putative predictive biomarkers from peripheral blood (PB) or tumor, including tumor PD-L1 expression, absolute lymphocyte count (ALC) and PB myeloid derived suppressor cells (MDSC) were evaluated. Pharmacodynamic changes in activated and effector T cells were also assessed. Methods: Tumor PD-L1 membrane expression was assessed in archival FFPE specimens by immunohistochemistry (28-8 PD-L1 antibody). ALC was measured in serial PB samples; changes in the percentage, number and phenotype of activated CD4+ and CD8+T cells and MDSC were characterized by flow cytometry. Results: PD-L1 expression was seen in 37% (10/27) of pts, using a cut-off of 5% tumor cell membrane staining. Objective responses (OR) were seen in pts with both PD-L1 negative (8/17) and PD-L1 positive (4/10) tumors. Relative to baseline, a rise in ALC was not detected, but phenotypic changes in PB T-cell subsets, including increases in the percentage of CD4 and CD8 expressing HLA-DR, ICOS and/or Ki67 were seen with combination therapy. Low ALC (<1.0 at wk 6-7) did not preclude OR as 3 of 12 pts with low ALC responded. Of pts evaluated, OR with ≥80% reduction in tumor burden at 12 wk were seen in pts with a low frequency of pretreatment PB MDSC (3/7) but no OR were seen in pts with high MDSC (0/6). Conclusions: In this small subset of pts,OR were seen independent of PD-L1 or ALC status in contrast to prior observations with nivolumab or ipilimumab, respectively. Thus, the immune response generated by combination therapy may have unique features compared to either monotherapy. The relationship between frequency of PB MDSC and reduction in tumor burden will be further explored. Further efforts in this study and in future phase III randomized studies will investigate these and other phenotypic changes in immune cell populations and their relationship to patterns of clinical activity. Clinical trial information: NCT01024231.

scholarly journals Pembrolizumab with low-dose carboplatin for recurrent platinum-resistant ovarian, fallopian tube, and primary peritoneal cancer: survival and immune correlates

2021 ◽  
Vol 9 (9) ◽  
pp. e003122
Author(s):  
John B Liao ◽  
William R Gwin ◽  
Renata R Urban ◽  
Katie M Hitchcock-Bernhardt ◽  
Andrew L Coveler ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
T Cells ◽  
T Cell ◽  
Fallopian Tube ◽  
Objective Response ◽  
Tumor Burden ◽  
Primary Peritoneal Cancer ◽  
Peritoneal Cancer ◽  
Immune Correlates ◽  
Platinum Resistant

BackgroundAnti-programmed death 1 (PD1)/programmed cell death ligand 1 (PD-L1) therapies have shown modest activity as monotherapy in recurrent ovarian cancer. Platinum chemotherapies induce T-cell proliferation and enhance tumor recognition. We assessed activity and safety of pembrolizumab with carboplatin in recurrent platinum-resistant ovarian cancer.Patients and methodsThis phase I/II, single-arm clinical trial studied concurrent carboplatin and pembrolizumab in recurrent platinum-resistant ovarian, fallopian tube, and primary peritoneal cancer. Primary platinum refractory patients were excluded. Patients were treated after progression on subsequent non-platinum systemic therapy after becoming platinum resistant or refractory. Pembrolizumab 200 mg was given on day 1 and carboplatin area under the curve 2 on days 8 and 15 of a 3-week cycle until progression. Imaging was assessed by blinded independent review. PD-L1 expression was assessed by immunohistochemistry. Flow cytometry on peripheral blood mononuclear cells was performed for CD3, CD4, CD8, PD1, CTLA4 and Ki67.ResultsThe most common treatment-related adverse events were lymphopenia (18%) and anemia (9%) with most being grade 1 or 2 (93%). Of 29 patients treated, 23 patients were evaluable for best objective response: 10.3% (95% CI 2.2 to 27.4) had partial response (PR), 51.7% (95% CI 32.5 to 70.6) had stable disease (SD). 56.5% of patients had decreases in target lesions from baseline. All PD-L1-positive patients achieved PR (3/7, 42.8%) or SD (4/7, 57.2%). Median progression-free survival was 4.63 months (95% CI 4.3 to 4.96). Median OS was 11.3 months (95% CI 6.094 to 16.506). Peripheral CD8+PD1+Ki67+ T cells expanded after 3 (p=0.0015) and 5 (p=0.0023) cycles. CTLA4+PD1+CD8+ T cells decreased through the course of treatment up to the 12th cycle (p=0.004). When stratified by ratio of peripheral CD8+PD1+Ki67+ T cells to tumor burden at baseline, patients with a ratio ≥0.0375 who had a significantly longer median OS of 18.37 months compared with those with a ratio <0.0375 who had a median OS of 8.72 months (p=0.0099). No survival advantage was seen with stratification by tumor burden alone (p=0.24) or by CD8+PD1+Ki67+ T cells alone (p=0.53).ConclusionsPembrolizumab with carboplatin was well-tolerated and active in recurrent platinum-resistant ovarian cancer. A ratio of peripheral T-cell exhaustion to radiographic tumor burden may identify patients more likely to benefit from this chemoimmunotherapy.Trial registration numberNCT03029598.

scholarly journals 669 Lactate uptake through MCT11, a novel monocarboxylate transporter, enforces dysfunction in terminally exhausted T cells

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A697-A697
Author(s):  
Ronal Peralta ◽  
Greg Delgoffe
Keyword(s):  
T Cells ◽  
Lactic Acid ◽  
Tumor Burden ◽  
B16 Melanoma ◽  
T Cell Subsets ◽  
Monocarboxylate Transporter ◽  
Acid Uptake ◽  
Ribonucleoprotein Complexes ◽  
Lactate Uptake ◽  
Marker Expression

BackgroundUpon infiltration into tumors, T cells experiencing persistent antigen stimulation progressively differentiate into a state of dysfunction, known as exhaustion. Exhausted T cells are characterized by the sustained upregulation of co-inhibitory molecules and reduced effector cytokine production. Additionally, exhausted T cells exist in a state of metabolic dysfunction in the tumor microenvironment (TME), due to disrupted mitochondrial biogenesis, hypoxia and lack of metabolites. Highly glycolytic tumor and stromal cells outcompete T cells for glucose, and secrete lactate into the TME, acidifying the extracellular space. Recent studies have shown lactate can be metabolized by tumor infiltrating Tregs and macrophages. We hypothesized that CD8+ tumor-infiltrating lymphocytes (TIL) may also take up lactate as an alternative carbon source to meet their metabolic demands.MethodsFor lactate uptake experiments, B16 melanoma single cell suspensions from B6 mice were loaded with the pH sensitive dye pHrodo, then pulsed with 5µM lactic acid. MCT11 KO OT-I T cells were generated via transfection of Slc16a11 sgRNA-Cas9 ribonucleoprotein complexes, and adoptively transferred into B16-OVA bearing mice.ResultsRNA sequencing and flow cytometry data from CD8+ T cell subsets in the TME revealed MCT11 (encoded by Slc16a11), a monocarboxylate transporter (MCT) only recently discovered, to be highly and uniquely expressed in terminally exhausted T cells (Tex). As lactate is an abundant monocarboxylate in tumors, we asked whether MCT11 supports lactate uptake into Tex cells. Antibody blockade of MCT11 resulted in reduced lactic acid uptake, but whether lactic acid promoted or inhibited effector function. Intriguingly, overexpression of MCT11 in OT-I T cells adoptively transferred into B16-OVA bearing mice resulted in accelerated exhaustion: increased co-inhibitory marker expression and decreased TNFa and IFN production. Conversely, knockdown of MCT11 in the same model resulted in decreased co-inhibitory marker expression and increased TNFa and IFN production. Further, MCT11 KO OT-I T cells used therapeutically had decreased tumor burden over mice treated with control OT-I T cells. As MCT11's uptake function was blocked with an antibody, we also used the antibody therapeutically, revealing that single-agent MCT11 antibody treatment reduced tumor burden and increased survival in B16 melanoma bearing mice.ConclusionsOur data support a model where exhausted CD8+ T cells upregulate MCT11, which renders them sensitive to toxic lactic acid in the TME. Our data suggest MCT11 could be deleted on therapeutic T cells or blocked using an antibody on endogenous T cells to render exhausted T cells impervious to lactic acid such and promote tumor eradication.

REGOMUNE: A phase II study of regorafenib plus avelumab in solid tumors—Results of the non-MSI-H metastatic colorectal cancer (mCRC) cohort.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 4019-4019 ◽  
Author(s):  
Sophie Cousin ◽  
Carine A. Bellera ◽  
Jean Philippe Guégan ◽  
Carlos A. Gomez-Roca ◽  
Jean-Philippe Metges ◽  
...  
Keyword(s):  
T Cells ◽  
Phase Ii ◽  
Cd8 T Cells ◽  
Objective Response ◽  
Previous Treatment ◽  
Progression Free Survival ◽  
Treatment Interruption ◽  
Median Number ◽  
Tumor Burden ◽  
Open Label

4019 Background: Regorafenib (R) has been shown to modulate anti-tumor immunity by different mechanisms including reduction of tumor-associated macrophages (TAMs). Synergy between R and anti–PD-1/PD-L1 antibodies has been shown in pre-clinical models. Methods: This is a single-arm open-label multicentric phase II trial assessing the efficacy and safety of R (160 mg QD 3weeks/4) + Avelumab (A) (10 mg/kg every 2 weeks) combination in non MSI-H mCRC patients (pts). The primary endpoint was the confirmed objective response rate, based on central review according to RECIST 1.1. Secondary endpoints included: 1-year progression free survival (PFS), 1-year overall survival (OS), and Safety using NCI-CTCAE v5.0. Correlative studies were planned from pts tumor samples obtained at baseline and C2D1. Results: Between Nov. 2018 and Oct. 2019, 48 pts were enrolled in 4 centers. Median age was 61.8 (range: 26.3-78.7). Median follow-up was: 7.2 months. Median number of previous treatment lines was: 3 (range: 1-7). 41 (87.2%) pts experienced at least 1 dose modification or treatment interruption. The most common grade 3/4 adverse events were palmar-plantar erythro-dysesthesia syndrome (29.8%), hypertension (23.4%) and diarrhea (12.8%). No death was related to the treatment. Among 40 pts who had at least one imaging tumor assessment, 12 (30%) had reduction in tumor burden. Best response was stable disease for 23 pts (57.5%) and progressive disease for 17 pts (42.5%). The median PFS and OS were 3.6 months (CI95%: [1.8 – 5.4]) and 10.8 months (CI95%: [5.9 – NA]) respectively. Baseline tumor samples and paired biopsies were available for 24 and 15 pts respectively. High infiltration by TAMs at baseline was significantly associated with adverse outcome (PFS: 1.9 vs 3.7 months, p=0.045; OS: 4.8 months vs NR, p=0.027). Increased tumor infiltration by CD8+ at C2D1 compared to baseline was significantly associated with better PFS (p=0.011). Combining low TAMs infiltration and low tumor cells to CD8+ T cells distance enabled the identification of a subgroup of pts (n= 6/24, 25%) more likely to benefit from R+A combination: median PFS: 5.3 vs 1.9 months (p=0.037); median OS: NR vs 5.3 months (p=0.02). Conclusions: The R+A combination achieved PFS and OS that compared favourably with historical data of R alone in this clinical setting. High-resolution analysis of tumor samples identified a composite score based on TAMs infiltration and tumor cell to CD8+ T cells distance which could be used as a biomarker in further studies investigating this approach in mCRC pts. Clinical trial information: NCT03475953 .

Open-Label Phase III Trial of Panitumumab Plus Best Supportive Care Compared With Best Supportive Care Alone in Patients With Chemotherapy-Refractory Metastatic Colorectal Cancer

2007 ◽  
Vol 25 (13) ◽  
pp. 1658-1664 ◽  
Author(s):  
Eric Van Cutsem ◽  
Marc Peeters ◽  
Salvatore Siena ◽  
Yves Humblet ◽  
Alain Hendlisz ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Supportive Care ◽  
Metastatic Colorectal Cancer ◽  
Disease Progression ◽  
Human Monoclonal Antibody ◽  
Objective Response ◽  
Response Rates ◽  
Best Supportive Care ◽  
Phase Iii ◽  
Tumor Cell Membrane

PurposePanitumumab is a fully human monoclonal antibody directed against the epidermal growth factor receptor (EGFR). We compared the activity of panitumumab plus best supportive care (BSC) to that of BSC alone in patients with metastatic colorectal cancer who had progressed after standard chemotherapy.Patients and MethodsWe randomly assigned 463 patients with 1% or more EGFR tumor cell membrane staining, measurable disease, and radiologic documentation of disease progression during or within 6 months of most recent chemotherapy to panitumumab 6 mg/kg every 2 weeks plus BSC (n = 231) or BSC alone (n = 232). Tumor assessments by blinded central review were scheduled from week 8 until disease progression. The primary end point was progression-free survival (PFS). Secondary end points included objective response, overall survival (OS), and safety. BSC patients who progressed could receive panitumumab in a cross-over study.ResultsPanitumumab significantly prolonged PFS (hazard ratio [HR], 0.54; 95% CI, 0.44 to 0.66, [P < .0001]). Median PFS time was 8 weeks (95% CI, 7.9 to 8.4) for panitumumab and 7.3 weeks (95% CI, 7.1 to 7.7) for BSC. Mean (standard error) PFS time was 13.8 (0.8) weeks for panitumumab and 8.5 (0.5) weeks for BSC. Objective response rates also favored panitumumab over BSC; after a 12-month minimum follow-up, response rates were 10% for panitumumab and 0% for BSC (P < .0001). No difference was observed in OS (HR, 1.00; 95% CI, 0.82 to 1.22), which was confounded by similar activity of panitumumab after 76% of BSC patients entered the cross-over study. Panitumumab was well tolerated. Skin toxicities, hypomagnesaemia, and diarrhea were the most common toxicities observed. No patients had grade 3/4 infusion reactions.ConclusionPanitumumab significantly improved PFS with manageable toxicity in patients with chemorefractory colorectal cancer.

scholarly journals Predictors of Efficacy in Chinese Patients with Severe Aplastic Anemia Treated with Eltrombopag and Intensive Immunosupressive Therapy

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 1115-1115
Author(s):  
Ruixin Li ◽  
Guangsheng He ◽  
Xi Chen ◽  
Zhengyuan Liu ◽  
Yan Yang ◽  
...  
Keyword(s):  
T Cells ◽  
Aplastic Anemia ◽  
Roc Curve ◽  
Lymphocyte Count ◽  
East Asian ◽  
T Cell Subsets ◽  
Phase Iii ◽  
Chinese Patients ◽  
Autoreactive T Cells ◽  
Immunosupressive Therapy

Abstract Prospective trials showed the clinical efficacy of eltrombopag in refractory/relapsed aplastic anemia (AA), with up to 40% hematologic improvement [1]. Moreover, eltrombopag was combined with frontline immunosupressive therapy (IST) consisited of antithymocyte immunoglobulin (ATG) and cyclosporin (CsA), with an overall response rate exceeding 80% [2]. The metabolism of eltrodopag is different in disparate population. Currently, the recommended dose is 75 mg/d for East Asian populations [2], Pretreatment clinical and laboratory characteristics predicting eltrombopag response are still unclear in severe AA (SAA) patients of real-world in East Asian. From May 2014 to December 2020, 59 adult SAA patients were treated with IST (r-ATG, 3.5mg/kg/d × 5d and CsA 3-5 mg/kg/d) in conjunction with eltrodopag at the dose of 75 mg/d from day 1 until 6 months. We used Receiver Operating Characteristic (ROC) curve to predict the factors of the efficacy of eltrombopag. Median follow-up was 13 months (6 month to 29 months). Overall 45 patients (76%) responded to eltrombopag, including 16 patients (27%) who achieved complete response (CR) and 29 patients (49%) who achieved partial response (PR), whist 14 patients were non-remission (NR) according to the criteria of the European Group for Blood and Marrow Transplantation (EBMT) [3]. The severity (P=0.032), infection (P=0.039) and lymphocyte count (P=0.021), as well as reticulocyte percentage (P=0.002) were different significantly between groups before the treatment (Table 1). Yet, the median age (38 years and 50.5 years) and median time from diagnosis to treatment (16 d and 27.5 d) are comparable. There was no significant difference in the count of platelet and T cell subsets of peripheral blood. ROC curve was used as one model to predict factors linked to the effects of eltrodopag in 6 months. The lymphocyte count (P=0.042, AUC=0.721, 95%CI 0.537-0.904), the percentage of reticulocyte (P=0.007, AUC=0.793, 95%CI 0.631-0.955), and red cell distribution width - coefficient of variation (RDW-CV) (P=0.042, AUC=0.721, 95%CI 0.493-0.948) were positively correlated with the efficacy of eltrombopag (Table 2, Figure 1). Discussion It has been reported that moderate diseaseand lymphoid marrow infiltration were related with the response to eltrombopag in older AA patients [4]. Scheinberg et al. has showed that predictive factors related to IST of 6th month were including the age, lymphocyte count and reticulocyte count [5]. We found that the lymphocyte count, the percentage of reticulocytes and RDW-CV were related with response. The increase of RDW-CV is related to production of reticulocyte. A higher lymphocyte count, the percentage of reticulocytes and RDW-CV may indicate better residual marrow function. Lymphocyte count is also associated with abnormal immunity. Hematopoietic recovery of SAA depends on IST involving elimination of autoreactive T cells that target progenitor cells in the bone marrow, and sufficient residual stem cells to support blood cell production after IST. IST combined with eltrombopag could eradicate autoreactive T cells and promote hematopoiesis simultaneously, thereby, the relevant indicators for predicting efficacy also reflect this related status. This study was limited by its retrospective nature, small cohorts, an absence of randomization a treatment comparator, and IST was based on r-ATG and CsA. In preliminar conclusion, the pretreatment lymphocyte count, the percentage of reticulocytes and RDW-CV together serve as a simple predictor of response following IST combined with eltrombopag for Chinese patients with SAA. Reference [1] Olnes MJ, et al. Eltrombopag and improved hematopoiesis in refractory aplastic anemia. N Engl J Med. 2012;367(3):11-19. [2] Townsley DM, et al. Eltrombopag Added to Standard Immunosuppression for Aplastic Anemia [J]. N Engl J Med, 2017, 376 (16): 1540-1550. [3] de Latour, RP, et al. Results of the EBMT SAAWP Phase III Prospective Randomized Multicenter RACE Study of Horse ATG and Ciclosporin with or without Eltrombopag in naive SAA patients. EBMT 2020 abstract O018. [4] Fattizzo B, et al. Clinical and morphological predictors of outcome in older aplastic anemia patients treated with eltrombopag. Haematologica. 2019 Nov;104(11): e494-e496. [5] Scheinberg P,et al. Predicting response to immunosuppressive therapy and survival in severe aplastic anaemia. Br J Haematol. 2009 Jan;144(2):206-16. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

scholarly journals Radiotherapy Priming Chimeric Antigen Receptor T Cell Therapy Is a Safe and Promising Approach in Relapsed/Refractory Diffuse Large B Cell Lymphoma Patients with High Tumor Burden

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2961-2961 ◽  
Author(s):  
Changju Qu ◽  
Nana Ping ◽  
Qian Wu ◽  
Liqing Kang ◽  
Fan Xia ◽  
...  
Keyword(s):  
T Cells ◽  
B Cell ◽  
Objective Response ◽  
B Cell Lymphoma ◽  
Tumor Burden ◽  
Neurological Toxicity ◽  
Car T Cells ◽  
High Tumor Burden ◽  
Large B Cell Lymphoma ◽  
Car T

Abstract Background: Chemoresistance is a core challenge in successful treatment of diffuse large B cell lymphoma (DLBCL). Chimeric antigen receptor T cells (CAR-T) therapy, as a novel immunotherapy modality, demonstrates impressive efficacy and durable remissions in relapsed/refractory(R/R) B-cell malignancies including DLBCL. However, CAR-T therapy is also associated with potentially fatal toxicities, including cytokine release syndrome (CRS) and neurological toxicities which limit the clinical application of CAR-T therapy in R/R DLBCL with high tumor burden. How to improve the prognosis of this population is urgently underway. Here, we conducted a trial testing efficacy and toxicities of CAR-T therapy in R/R lymphoma patients (This study is registered at www.clinicaltrials.gov as NCT03196830). Methods:Human T cells were collected from autologous/allogenous peripheral blood mononuclear cells (PBMC) . CD3+T cells were separated from PBMS of patients or donors by degradable anti-CD3 magnetic microbeads followed by 24h stimulation with CD3 and CD28 monoclonal antibody (5ug/ml). Then CD3+T cells were transduced with lentivirus particles incorporated with a humanized CAR construct targeting CD19, CD20 and CD22 and further expanded for 7 to 10 days in vitro. The transfection efficacy, ratio of CD4+ versus CD8+, antitumor activities, pathogen detection as well as cytokines releasing of CAR-T cells were evaluated before infusion to patients. In this ongoing trial, 14 patients were diagnosed as R/R DLBCL with high tumor burden. Two debulking conditioning regimens including intensive combined chemotherapy or radiation (40 gray in 20 fractions) were carried out before CAR-T therapy followed by sequential FC regimen (cyclophosphamide 300mg/m2 and fludarabine 30mg/m2 X 3d) for lymphodepletion chemotherapy. Two days after FC regimen, autologous/allogenous CAR-T cells targeting CD19 and CD20 or CD22 provided by the unicar-therapy bio-medicine technology co.(Shanghai, China) at average dose of 1-2×107 cells for each target per kilogram(kg) were infused within 3 days. Results: 14 R/R DLBCL patients with high tumor burden were enrolled in the study. Patients ranged from 39 to 66 years of age had received two to four prior lines of therapy. Out of the 14 patients, 7 patients received intensive second-line chemotherapy (median age, 46 years) and 7 received radiotherapy (median age, 63years) to debulking tumor after leukapheresis and during CAR-T cells preparation. All Adverse Events occurring within 30 days of CAR-T cells infusion were graded and reported for the 14(100%) treated patients. All patients experienced CAR-T-related CRS of any grade with severe CRS (grade 3/4/5) reported in all patients of chemotherapy cohort experienced and mild CRS (grade 1/2) reported in all patients of radiation cohort. 4 patients (57.1%) in chemotherapy cohort manifested with neurological toxicity while no patient in radiation cohort manifested with neurological toxicity. Comparable hematological toxicity as well as non-hematological and non-neurological toxicity were observed in two groups. Four of seven (57.1%) patients achieved an objective response after CAR-T infusion, with three of seven (42.9%) achieving a CR in chemotherapy cohort, while seven of seven (100%) achieved an objective response after CAR-T therapy, with four of seven (57.1%) achieving a CR in radiation cohort. Conclusions:Our clinical trial indicates that compared to intensive second-line chemotherapy, radiation is a better approach to enhancing efficacy and decreasing toxicity of CAR-T therapy in R/R DLBCL patients with high tumor burden. Radiotherapy in combination with CAR-T cell infusion may be the optimal alternative treatment model of R/R DLBCL with high tumor burden. Disclosures No relevant conflicts of interest to declare.

scholarly journals Therapy of 4s Chimeric Antigen Receptor T Cells Achieves Long-Term Disease-Free Survival with No Severe CRS or Cres in Patients with Relapsed and Refractory Acute Lymphoblastic Leukemia

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2696-2696 ◽  
Author(s):  
Sanfang Tu ◽  
Rui Huang ◽  
Lan Deng ◽  
Xuan Zhou ◽  
Yanjie He ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Lymphoblastic Leukemia ◽  
Objective Response ◽  
Disease Free Survival ◽  
Tumor Burden ◽  
Fourth Generation ◽  
Free Survival ◽  
Car T ◽  
Disease Free

Abstract Background: CD19 targeting chimeric antigen receptor T cells(CART19) therapy have shown great therapeutic potential in relapsed and refractory B cell acute lymphoblastic leukemia (ALL), but associated with risk of life-threatening adverse effects as severe cytokine release syndrome (sCRS) and CAR-T-cell-related encephalopathy syndrome (CRES).It's been reported that high leukemia burden before CART therapy, and high does infused CART cells are associated with severity of CRS and CRES. To decrease the risk of severe adverse effect, we applied integrated therapeutic strategy of using fourth generation CART cells , reducing leukemia blasts burden in bone marrow, and decreasing the dose of infused CART cells (www.clinicaltrials.gov; #NCT03407859 and #NCT03125577 ). Methods: Between May 23, 2016 and July 2, 2018,the trial enrolled 20 patients (pts) who were exhausted with all available treatment options, life expectancy >2 months,CD19-positive and diagnosis of B lineage ALL.T cells were apheresis collected and transduced with an apoptosis-inducible, safety-engineered lentivector CAR with the following intracellular signaling domains: CD28/CD27/CD3ζ-iCasp9 (4SCAR). In vitro amplication of CART was not performed. In pts with bone marrow blasts exceeding 50.0%, VDCP or similar chemotherapy was given to reduce the tumor burden, and then received FC conditioning regimen (FLU 30mg/m2, d1-3; CTX 300mg/m2, d1-3), while FC regimen was directly carried out in pts with bone marrow blasts less than 50.0%.In this trial, Pts received single CD19-targeted CARTs or multi-CARTs targeting CD19 and an additional antigen of CD22 or CD123.The level of CAR-T cells and cytokines in peripheral blood, as well as tumor burden was measured after infusion. Results: 20 pts were enrolled and infused with CAR-T cells. The median age is 37.5 (16-67) years old. Of these pts, 5 had prior HSCT and 14 had adverse genetic abnormalities, including 4 pts (20%) who were Philadelphia chromosome-positive(Ph+). All pts were previously treated with 2-22 courses of cytotoxic chemotherapy regimens. The overall objective response rate was 85%(17/20), and the complete response(CR) rate was 80%(16/20). The complete remission rate of 12 pts receiving single CD19-targeted CART therapy was 83 %(10/12), while 33%(4/12) of them had disease relapse at 6 months after infusion. Of the 7 people who received multi-CARTs infusion, 71%(5/7) achieved complete remission, with relapse rate of 29%(2/7) at 6 months after infusion. 3 pts who relapsed post transplantation received combination therapy of anti-CD19 CART and anti-CD123 CART, and all achieved minimal residual disease-negative CR within 1 month after CART infusion, 2 of whom maintained disease-free survival for 7 months and 11 months to date, respectively. Among the 7 people who underwent HSCT after achieving CR, 6 of them maintained disease-free survival for 3 months to 9 months. At a median follow-up of 115.5 days (ranging from14 to 384), the median overall survival was 269 days and the median event-free survival was 232 days. During treatment and follow-up, the most common adverse events were grade 1-2 cytokine release syndrome (CRS), with an incidence of 55%.No grade 3 or higher CRS was observed.12 pts were infused with a dose equal to or exceeding 5*10^5/kg, 10 of whom had CRS response. While only 2 of the 8 pts who received the infusion dose of less than 5*10^5/kg had CRS reaction and both of them were grade 1 CRS, suggesting low CAR-T cell doses decrease the risk of CRS (P=0.009). Interestingly, the objective response rate did not differ significantly between the low dose and high dose group. Conclusions: Based on fourth generation CART system, a therapeutic strategy of low tumor burden and low CART infusion dose shows a safer profiling while remaining potent efficacy against leukemia. Disclosures No relevant conflicts of interest to declare.

Association of tumor PD-L1 expression and immune biomarkers with clinical activity in patients (pts) with advanced solid tumors treated with nivolumab (anti-PD-1; BMS-936558; ONO-4538).

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 3016-3016 ◽  
Author(s):  
Joseph Grosso ◽  
Christine E. Horak ◽  
David Inzunza ◽  
Diana M. Cardona ◽  
Jason S. Simon ◽  
...  
Keyword(s):  
T Cell Activation ◽  
Cell Activation ◽  
Mononuclear Cells ◽  
Objective Response ◽  
Predictive Biomarkers ◽  
Phase Iii ◽  
Clinical Activity ◽  
Post Dose ◽  
Peripheral Blood Mononuclear ◽  
Immune Biomarkers

3016 Background: The immune checkpoint receptor programmed death-1 (PD-1) negatively regulates T-cell activation. In a phase I study, nivolumab, a PD-1 receptor blocking antibody, demonstrated durable clinical activity. Evaluation of the expression of the PD-1 ligand, PD-L1, by IHC with the 5H1 Ab suggested a correlation between pretreatment tumor PD-L1 expression and clinical response (Topalian et al, NEJM 2012). Methods: 304 pts with non-small cell lung cancer (NSCLC, n=127), melanoma (MEL, n=107), renal cell (RCC, n=34), colorectal (n=19) or prostate cancer (n=17) received nivolumab between 2008-2012 (0.1−10 mg/kg IV Q2W) during dose escalation and/or cohort expansion. Formalin-fixed paraffin-embedded tumor tissue and peripheral blood mononuclear cells (PBMC) were analyzed to explore potential pharmacodynamic/ predictive biomarkers associated with nivolumab therapy. Tumor surface PD-L1 expression was evaluated by IHC using an automated assay based on a sensitive and specific PD-L1 mAb (28-8) distinct from 5H1. PD-L1 positivity (PD-L1+) was defined as ≥5% cell membrane staining of any intensity. Lymphocyte subsets in PBMC were measured using flow cytometry. Results: Tumor membrane PD-L1 was measured in 101 MEL and NSCLC pts. 17/38 (45%) of MEL and 31/63 (49%) of NSCLC biopsies were PD-L1+. A numerically higher objective response rate (ORR), longer progression-free survival (PFS), and overall survival (OS) was seen with PD-L1+ in MEL pts (Table).Analysis of the association of PD-L1 expression with ORR, PFS and OS in NSCLC is ongoing. A correlative analysis of pt response with pre-/post-dose levels of lymphocytes will be presented. Conclusions: These data, using a novel, automated PD-L1 IHC assay and mAb, support the hypothesis of tumor PDL1+ predicting activity of nivolumab in advanced cancer, which is being prospectively assessed in phase III trials. Clinical trial information: NCT00730639. [Table: see text]

Efficacy and safety of gemcitabine in combination with TH-302 compared with gemcitabine in combination with placebo in previously untreated patients with metastatic or locally advanced unresectable pancreatic adenocarcinoma: The MAESTRO trial.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. TPS4148-TPS4148 ◽  
Author(s):  
Eric Van Cutsem ◽  
Robert J. Fram ◽  
Michael Schlichting ◽  
David P. Ryan
Keyword(s):  
Pancreatic Adenocarcinoma ◽  
Controlled Trial ◽  
Performance Status ◽  
Objective Response ◽  
Locally Advanced ◽  
Predictive Biomarkers ◽  
Treatment Discontinuation ◽  
Phase Iii ◽  
Ecog Performance Status ◽  
Double Blind

TPS4148 Background: Tumors often consist of highly hypoxic subregions that are resistant to chemotherapy and radiotherapy. The investigational hypoxia-targeted drug TH-302 is reduced at its nitroimidazole group, and under hypoxic conditions releases the DNA alkylator bromo-isophosphoramide mustard (Br-IPM). A randomized Phase IIb trial of TH-302 in pts with metastatic or locally advanced unresectable pancreatic adenocarcinoma (PDAC) confirmed a significant PFS improvement (p=0.008) in pts treated with TH-302 at 340 mg/m2+ gemcitabine compared with gemcitabine alone (Borad et al, ESMO 2012). Skin and mucosal toxicities, mainly Grade 1/2, and myelosuppression (thrombocytopenia, neutropenia and anemia) were the most common AEs related to TH-302 and did not lead to increases in treatment discontinuation. Grade 3/4 myelosuppression was more frequent in the TH-302 + gemcitabine arm. AEs leading to treatment discontinuation as well as non-hematological serious AEs were balanced across arms. Methods: This is a Phase III, randomized, double-blind, placebo-controlled trial (NCT01746979) of gemcitabine + TH-302 compared with gemcitabine + placebo in pts with locally advanced unresectable or metastatic PDAC. The study is designed to detect a 25% risk reduction of death with 90% power and two-sided alpha of 5%. A total of 660 pts are planned to be randomized 1:1. Key eligibility criteria include histologically or cytologically confirmed disease, no prior chemotherapy or systemic therapy (except as specified in the protocol), ECOG performance status 0 – 1, and bilirubin ≤ 1.5x upper limit of normal. Randomized pts receive TH-302 + gemcitabine or gemcitabine + placebo in 4-week cycles until progressive disease, intolerable toxicity, or pt withdrawal. The primary objective is to evaluate OS. Secondary objectives include PFS, objective response, and disease control; safety and tolerability; pt-reported QoL and pain; CA 19-9 levels and PK of TH-302; exploratory pharmacogenomic markers and potential predictive biomarkers. Enrollment to the study is ongoing. Clinical trial information: NCT01746979.

Randomized Phase III Trial of Temsirolimus and Bevacizumab Versus Interferon Alfa and Bevacizumab in Metastatic Renal Cell Carcinoma: INTORACT Trial

2014 ◽  
Vol 32 (8) ◽  
pp. 752-759 ◽  
Author(s):  
Brian I. Rini ◽  
Joaquim Bellmunt ◽  
Jill Clancy ◽  
Kongming Wang ◽  
Andreas G. Niethammer ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Combination Therapy ◽  
Cell Carcinoma ◽  
Metastatic Renal Cell Carcinoma ◽  
Renal Cell ◽  
Clear Cell ◽  
Objective Response ◽  
Interferon Alfa ◽  
Phase Iii ◽  
Cancer Center

PurposeTo prospectively determine the efficacy of combination therapy with temsirolimus plus bevacizumab versus interferon alfa (IFN) plus bevacizumab in metastatic renal cell carcinoma (mRCC).Patients and MethodsIn a randomized, open-label, multicenter, phase III study, patients with previously untreated predominantly clear-cell mRCC were randomly assigned, stratified by prior nephrectomy and Memorial Sloan-Kettering Cancer Center prognostic group, to receive the combination of either temsirolimus (25 mg intravenously, weekly) or IFN (9 MIU subcutaneously thrice weekly) with bevacizumab (10 mg/kg intravenously, every 2 weeks). The primary end point was independently assessed progression-free survival (PFS).ResultsMedian PFS in patients treated with temsirolimus/bevacizumab (n = 400) versus IFN/bevacizumab (n = 391) was 9.1 and 9.3 months, respectively (hazard ratio [HR], 1.1; 95% CI, 0.9 to 1.3; P = .8). There were no significant differences in overall survival (25.8 ν 25.5 months; HR, 1.0; P = .6) or objective response rate (27.0% ν 27.4%) with temsirolimus/bevacizumab versus IFN/bevacizumab, respectively. Patients receiving temsirolimus/bevacizumab reported significantly higher overall mean scores in the Functional Assessment of Cancer Therapy–Kidney Symptom Index (FKSI) –15 and FKSI-Disease Related Symptoms subscale compared with IFN/bevacizumab (indicating improvement); however, no differences in global health outcome measures were observed. Treatment-emergent all-causality grade ≥ 3 adverse events more common (P < .001) with temsirolimus/bevacizumab were mucosal inflammation, stomatitis, hypophosphatemia, hyperglycemia, and hypercholesterolemia, whereas neutropenia was more common with IFN/bevacizumab. Incidence of pneumonitis with temsirolimus/bevacizumab was 4.8%, mostly grade 1 or 2.ConclusionTemsirolimus/bevacizumab combination therapy was not superior to IFN/bevacizumab for first-line treatment in clear-cell mRCC.

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