Immunopharmacologic response of patients with B-lineage acute lymphoblastic leukemia to continuous infusion of T cell–engaging CD19/CD3-bispecific BiTE antibody blinatumomab

T cell–engaging CD19/CD3-bispecific BiTE Ab blinatumomab has shown an 80% complete molecular response rate and prolonged leukemia-free survival in patients with minimal residual B-lineage acute lymphoblastic leukemia (MRD+ B-ALL). Here, we report that lymphocytes in all patients of a phase 2 study responded to continuous infusion of blinatumomab in a strikingly similar fashion. After start of infusion, B-cell counts dropped to < 1 B cell/μL within an average of 2 days and remained essentially undetectable for the entire treatment period. By contrast, T-cell counts in all patients declined to a nadir within < 1 day and recovered to baseline within a few days. T cells then expanded and on average more than doubled over baseline within 2-3 weeks under continued infusion of blinatumomab. A significant percentage of reappearing CD8+ and CD4+ T cells newly expressed activation marker CD69. Shortly after start of infusion, a transient release of cytokines dominated by IL-10, IL-6, and IFN-γ was observed, which no longer occurred on start of a second treatment cycle. The response of lymphocytes in leukemic patients to continuous infusion of blinatumomab helps to better understand the mode of action of this and other globally T cell–engaging Abs. The trial is registered with www.clinicaltrials.gov identifier NCT00560794.

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Immunopharmacodynamic response to blinatumomab in patients with relapsed/refractory B-precursor acute lymphoblastic leukemia (ALL).

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.15_suppl.7020 ◽

2013 ◽

Vol 31 (15_suppl) ◽

pp. 7020-7020 ◽

Cited By ~ 6

Author(s):

Andrea Schub ◽

Virginie Nägele ◽

Gerhard Zugmaier ◽

Christian Brandl ◽

Youssef Hijazi ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

B Cell ◽

T Cell Activation ◽

Cell Activation ◽

Lymphoblastic Leukemia ◽

Granzyme B ◽

Significant Proportion ◽

Target Cells ◽

Cell Counts

7020 Background: Blinatumomab is an anti-CD19/anti-CD3 bispecific T cell engager (BiTE) that induces target cell-dependent, polyclonal T cell activation and proliferation, resulting in redirected lysis of CD19+ target cells. Methods: In a phase 2 study, adult patients (N=36) with relapsed/refractory B-precursor ALL received continuous blinatumomab IV infusion for 28 days in ≤5 treatment/consolidation cycles. Whole blood and serum samples were collected throughout treatment and analyzed for lymphocyte subpopulations, cytokines, granzyme B, and blinatumomab serum concentrations. Results: Lymphocytes in all patients responded in a similar fashion. After infusion start, peripheral B cell counts dropped to ≤1 B cell/μL in <1 week and remained undetectable throughout treatment. Peripheral T cells showed a redistribution characterized by swift disappearance within the first 2-6 hrs and subsequent recovery to baseline within several days. Otherwise, T cell counts remained at least stable in most patients. In some patients even an expansion of the T cell compartments was observed, most likely due to specific proliferation of activated T cells but could not be defined as prerequisite for treatment efficacy. During the first infusion days, a significant proportion of T cells newly expressed the activation marker CD69, and the T cell effector molecule granzyme B was detectable in serum. Additionally, a transient cytokine release dominated by IL-10, IL-6 and IFN-γ was observed in most patients shortly after first infusion start, which was alleviated or absent in subsequent cycles. Blinatumomab serum steady state concentrations (mean±SD) were 198±61 pg/mL and 694±236 pg/mL at doses of 5 and 15 μg/m²/d, respectively, which is comparable to those from previous studies. Conclusions: Immunopharmacodynamic response to blinatumomab was characterized by B cell depletion, T cell activation and redistribution, and release of granzyme B and cytokines, suggesting T cell engagement according to the expected BiTE mode of action. The tested pharmacodynamic markers did not allow for predictive differentiation between patients achieving a hematologic response and those who did not. Clinical trial information: NCT01209286.

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Pre-B acute lymphoblastic leukemia cells may induce T-cell anergy to alloantigen

Blood ◽

10.1182/blood.v88.1.41.41 ◽

1996 ◽

Vol 88 (1) ◽

pp. 41-48 ◽

Cited By ~ 140

Author(s):

AA Cardoso ◽

JL Schultze ◽

VA Boussiotis ◽

GJ Freeman ◽

MJ Seamon ◽

...

Keyword(s):

T Cells ◽

Acute Lymphoblastic Leukemia ◽

T Cell ◽

B Cell ◽

Tumor Cells ◽

Lymphoblastic Leukemia ◽

Interleukin 2 ◽

Human Tumor ◽

Clinically Significant ◽

Antigen Presenting

Abstract Even if neoplastic cells express tumor associated antigens they still may fail to function as antigen presenting cells (APC) if they lack expression of one or more molecules critical for the induction of productive immunity. These cellular defects can be repaired by physiologic activation, transfection, or fusion of tumor cells with professional APC. Although such defects can be repaired, antitumor specific T cells may still fail to respond in vivo if they may have been tolerized. Here, human pre-B cell acute lymphoblastic leukemia (pre-B ALL) was used as a model to determine if primary human tumor cells can function as alloantigen presenting cells (alloAPC) or alternatively whether they induce anergy. In the present report, we show that pre-B cell ALL express alloantigen and adhesion molecules but uniformly lack B7–1 (CD80) and only a subset express B7–2 (CD86). Pre-B ALL cells are inefficient or ineffective alloAPC and those cases that lack expression of B7–1 and B7–2 also induce alloantigen specific T- cell unresponsiveness. Under these circumstances, T-cell unresponsiveness could be prevented by physiologic activation of tumor cells via CD40, cross-linking CD28, or signaling through the common gamma chain of the interleukin-2 receptor on T cells. Taken together, these results suggest that pre-B ALL may be incapable of inducing clinically significant T-cell-mediated antileukemia responses. This defect may be not only due to their inability to function as APC, but also due to their potential to induce tolerance. Attempts to induce clinically significant antitumor immune responses may then require not only mechanisms to repair the antigen presenting capacity of the tumor cells, but also reversal of tolerance.

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Chimeric antigen receptor T-cell neuropsychiatric toxicity in acute lymphoblastic leukemia

Palliative & Supportive Care ◽

10.1017/s147895151600095x ◽

2017 ◽

Vol 15 (4) ◽

pp. 499-503 ◽

Cited By ~ 12

Author(s):

Vasthie Prudent ◽

William S. Breitbart

Keyword(s):

T Cells ◽

Acute Lymphoblastic Leukemia ◽

T Cell ◽

B Cell ◽

Chimeric Antigen Receptor ◽

Current Literature ◽

Respiratory Insufficiency ◽

Lymphoblastic Leukemia ◽

Antigen Receptor ◽

Neuropsychiatric Toxicity

ABSTRACTChimeric antigen receptor T cells are used in the treatment of B-cell leukemias. Common chimeric antigen receptor T-cell toxicities can range from mild flu-like symptoms, such as fever and myalgia, to a more striking neuropsychiatric toxicity that can present as discrete neurological symptoms and delirium. We report here two cases of chimeric antigen receptor T-cell neuropsychiatric toxicity, one who presented as a mild delirium and aphasia that resolved without intervention, and one who presented with delirium, seizures, and respiratory insufficiency requiring intensive treatment. The current literature on the treatment and proposed mechanisms of this clinically challenging chimeric antigen receptor T-cell complication is also presented.

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Demonstration of functional CD40 in B-lineage acute lymphoblastic leukemia cells in response to T-cell CD40 ligand

Blood ◽

10.1182/blood.v87.12.5162.bloodjournal87125162 ◽

1996 ◽

Vol 87 (12) ◽

pp. 5162-5170 ◽

Cited By ~ 22

Author(s):

N Renard ◽

M Lafage-Pochitaloff ◽

I Durand ◽

V Duvert ◽

L Coignet ◽

...

Keyword(s):

T Cells ◽

Acute Lymphoblastic Leukemia ◽

T Cell ◽

Cd4 T Cells ◽

Cell Clone ◽

Lymphoblastic Leukemia ◽

Leukemic Cells ◽

Activated T Cells ◽

T Cell Clone ◽

B Lineage

Because activated T cells were previously shown to induce proliferation of human normal B-cell precursors (BCP) via the CD40 pathway, we investigated the effects of T cells on leukemic blasts isolated from patients with B-lineage acute lymphoblastic leukemia (BCP-ALL). An anti- CD3 activated human CD4+ T-cell clone was found to induce significant call proliferation in four of nine BCP-ALL samples analyzed. In one of these cases, the T-cell effect was clearly dependent on interaction between CD40 and its ligand. Accordingly, a more thorough analysis was performed on this particular leukemia (case 461, adult early pre-B-ALL, mBCR+, Philadelphia+, i(9q)+). Thus, autologous CD4+ T cells isolated from the patient were also able to induce CD40-dependent proliferation of the leukemic blasts. Analysis of the phenotype after coculture showed that, among the CD19+ cells, a proportion gradually lost expression of CD10 and CD34, whereas some cells acquired CD23. In addition, and in contrast with normal BCP, activated T cells promoted maturation of a subset of the case 461 leukemic cells into surface IgM+ cells. The leukemic origin of the cycling and the maturing cells was assessed by the presence of i(9q), a chromosomal abnormality associated with this leukemia and evidenced by fluorescence in situ hybridization. Taken together, these results show that leukemic BCP can be activated via CD40 but that not all cases display detectable stimulation in response to T cells despite their expression of CD40. In addition, the present data suggest that CD4+ T cells could potentially play a role in the physiology of BCP-ALL.

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CAR-T Cell Therapies: An Overview of Clinical Studies Supporting Their Approved Use against Acute Lymphoblastic Leukemia and Large B-Cell Lymphomas

International Journal of Molecular Sciences ◽

10.3390/ijms21113906 ◽

2020 ◽

Vol 21 (11) ◽

pp. 3906 ◽

Cited By ~ 4

Author(s):

Aamir Ahmad ◽

Shahab Uddin ◽

Martin Steinhoff

Keyword(s):

T Cells ◽

Acute Lymphoblastic Leukemia ◽

T Cell ◽

B Cell ◽

Clinical Studies ◽

Lymphoblastic Leukemia ◽

Car T Cells ◽

Car T Cell ◽

Car T ◽

Large B Cell

Chimeric Antigen Receptor (CAR)-T cell therapy is an exciting development in the field of cancer immunology, wherein immune T-cells from patients are collected, engineered to create ‘CAR’-T cells, and infused back into the same patient. Currently, two CAR-T-cell-based therapies, Tisagenlecleucel and Axicabtagene ciloleucel, are approved by FDA for the treatment of hematological malignancies, acute lymphoblastic leukemia and large B-cell lymphomas. Their approval has been a culmination of several phase I and II clinical studies, which are the subject of discussion in this review article. Over the years, CAR-T cells have evolved to be significantly more persistent in patients’ blood, resulting in a much-improved clinical response and disease remission. This is particularly significant given that the target patient populations of these therapies are those with relapsed and refractory disease who have often progressed on multiple therapies. Despite the promising clinical results, there are still several challenges that need to be addressed. Of particular note are the associated toxicities exemplified by cytokine release syndrome (CRS) and the neurotoxicity. CRS has been addressed by an FDA-approved therapy of its own—tocilizumab. This article focuses on the progress related to CAR-T therapy: the pertinent clinical studies and their major findings, their associated adverse effects, and future perspective.

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Pre-B acute lymphoblastic leukemia cells may induce T-cell anergy to alloantigen

Blood ◽

10.1182/blood.v88.1.41.bloodjournal88141 ◽

1996 ◽

Vol 88 (1) ◽

pp. 41-48 ◽

Cited By ~ 4

Author(s):

AA Cardoso ◽

JL Schultze ◽

VA Boussiotis ◽

GJ Freeman ◽

MJ Seamon ◽

...

Keyword(s):

T Cells ◽

Acute Lymphoblastic Leukemia ◽

T Cell ◽

B Cell ◽

Tumor Cells ◽

Lymphoblastic Leukemia ◽

Interleukin 2 ◽

Human Tumor ◽

Clinically Significant ◽

Antigen Presenting

Even if neoplastic cells express tumor associated antigens they still may fail to function as antigen presenting cells (APC) if they lack expression of one or more molecules critical for the induction of productive immunity. These cellular defects can be repaired by physiologic activation, transfection, or fusion of tumor cells with professional APC. Although such defects can be repaired, antitumor specific T cells may still fail to respond in vivo if they may have been tolerized. Here, human pre-B cell acute lymphoblastic leukemia (pre-B ALL) was used as a model to determine if primary human tumor cells can function as alloantigen presenting cells (alloAPC) or alternatively whether they induce anergy. In the present report, we show that pre-B cell ALL express alloantigen and adhesion molecules but uniformly lack B7–1 (CD80) and only a subset express B7–2 (CD86). Pre-B ALL cells are inefficient or ineffective alloAPC and those cases that lack expression of B7–1 and B7–2 also induce alloantigen specific T- cell unresponsiveness. Under these circumstances, T-cell unresponsiveness could be prevented by physiologic activation of tumor cells via CD40, cross-linking CD28, or signaling through the common gamma chain of the interleukin-2 receptor on T cells. Taken together, these results suggest that pre-B ALL may be incapable of inducing clinically significant T-cell-mediated antileukemia responses. This defect may be not only due to their inability to function as APC, but also due to their potential to induce tolerance. Attempts to induce clinically significant antitumor immune responses may then require not only mechanisms to repair the antigen presenting capacity of the tumor cells, but also reversal of tolerance.

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Humanized CD19-Targeted Chimeric Antigen Receptor (CAR) T Cells in CAR-Naive and CAR-Exposed Children and Young Adults With Relapsed or Refractory Acute Lymphoblastic Leukemia

Journal of Clinical Oncology ◽

10.1200/jco.20.03458 ◽

2021 ◽

pp. JCO.20.03458

Author(s):

Regina M. Myers ◽

Yimei Li ◽

Allison Barz Leahy ◽

David M. Barrett ◽

David T. Teachey ◽

...

Keyword(s):

T Cells ◽

Young Adults ◽

Acute Lymphoblastic Leukemia ◽

T Cell ◽

B Cell ◽

Chimeric Antigen Receptor ◽

Lymphoblastic Leukemia ◽

Car T Cell ◽

Car T ◽

Children And Young Adults

PURPOSE CD19-targeted chimeric antigen receptor (CAR)–modified T cells demonstrate unprecedented responses in B-cell acute lymphoblastic leukemia (B-ALL); however, relapse remains a substantial challenge. Short CAR T-cell persistence contributes to this risk; therefore, strategies to improve persistence are needed. METHODS We conducted a pilot clinical trial of a humanized CD19 CAR T-cell product (huCART19) in children and young adults with relapsed or refractory B-ALL (n = 72) or B-lymphoblastic lymphoma (n = 2), treated in two cohorts: with (retreatment, n = 33) or without (CAR-naive, n = 41) prior CAR exposure. Patients were monitored for toxicity, response, and persistence of huCART19. RESULTS Seventy-four patients 1-29 years of age received huCART19. Cytokine release syndrome developed in 62 (84%) patients and was grade 4 in five (6.8%). Neurologic toxicities were reported in 29 (39%), three (4%) grade 3 or 4, and fully resolved in all cases. The overall response rate at 1 month after infusion was 98% (100% in B-ALL) in the CAR-naive cohort and 64% in the retreatment cohort. At 6 months, the probability of losing huCART19 persistence was 27% (95% CI, 14 to 41) for CAR-naive and 48% (95% CI, 30 to 64) for retreatment patients, whereas the incidence of B-cell recovery was 15% (95% CI, 6 to 28) and 58% (95% CI, 33 to 77), respectively. Relapse-free survival at 12 and 24 months, respectively, was 84% (95% CI, 72 to 97) and 74% (95% CI, 60 to 90) in CAR-naive and 74% (95% CI, 56 to 97) and 58% (95% CI, 37 to 90) in retreatment cohorts. CONCLUSION HuCART19 achieved durable remissions with long-term persistence in children and young adults with relapsed or refractory B-ALL, including after failure of prior CAR T-cell therapy.

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B Cell Aplasia In a Patient with Relapsed B Cell Acute Lymphoblastic Leukemia Following Re-Induction and Consolidation with Autologous T Cells Genetically Targeted to the CD19 Antigen

Blood ◽

10.1182/blood.v116.21.3268.3268 ◽

2010 ◽

Vol 116 (21) ◽

pp. 3268-3268

Author(s):

Marco L Davila ◽

Clare Taylor ◽

Xiuyan Wang ◽

Jolanta Stefanski ◽

Malgorzata Olszewska ◽

...

Keyword(s):

Clinical Trial ◽

T Cells ◽

Stem Cell ◽

Acute Lymphoblastic Leukemia ◽

T Cell ◽

B Cell ◽

Induction Chemotherapy ◽

Lymphoblastic Leukemia ◽

High Dose ◽

Cell Acute Lymphoblastic Leukemia

Abstract Abstract 3268 Despite high initial remission rates following induction chemotherapy, most adults with B cell acute lymphoblastic leukemia (B-ALL) ultimately relapse and the overall prognosis is poor. In light of the overall poor outcomes seen with currently available chemotherapy regimens as well as allogeneic stem cell transplantation, novel and effective treatment approaches are needed for these patients. To this end, we have developed a program utilizing a patient's own T cells genetically modified ex vivo to express a chimeric antigen receptor (CAR), termed 19–28z, specific to the CD19 antigen expressed on normal B cells as well as most B-ALL tumors. In preclinical studies, human T cells modified to express the 19–28z CAR effectively eradicated systemic human B-ALL NALM-6 tumors in SCID-Beige mice. Based on these findings we have recently opened a phase I clinical trial (IRB #09-114) wherein patients with relapsed B-ALL are initially treated with re-induction chemotherapy followed by consolidation with high dose cyclophosphamide (3gm/m2) and a subsequent infusion of autologous T cells genetically modified to express the 19–28z CAR. Herein, we report the initial findings of the first patient treated on this clinical trial. This patient, a 67-year-old male, with B-ALL (normal cytogenetics), achieved a complete remission following induction chemotherapy with mitoxantrone and high-dose cytarabine. The patient remained in remission following treatment with vincristine (consolidation B) and cyclophosphamide (consolidation C). However, he was noted to have relapsed disease following consolidation cycle D with cytarabine and etoposide. At the time of relapse the patient was leukapheresed to obtain autologous T cells, and subsequently achieved a second remission following re-induction with a modified PEG-asparaginase, vincristine, and prednisone regimen. Upon recovery, the patient, as stipulated by the clinical trial, received lymphodepleting consolidation with high dose cyclophosphamide followed, 2 and 3 days later, by a split dose infusion of 3 × 106/kg autologous 19–28z+ T cells, the lowest planned T cell dose on this trial. Over the next 2 weeks, FACS and Q-PCR detected gene-modified T cells in the peripheral blood. Significantly, over the next 5 weeks, despite recovery of neutrophils and T cells, the patient exhibited a persistent B cell aplasia consistent with CD19-targeted cytotoxic activity of the infused autologous 19–28z+ T cells. The patient subsequently received an allogeneic stem cell transplant from a HLA-identical sibling effectively abrogating further analysis of modified T cell function. Despite this limitation, we conclude that following lymphodepleting chemotherapy, modified CD19-targeted T cells exhibit effective anti-CD19 cytotoxic activity, as demonstrated by the persistent B cell aplasia, in the clinical setting. These findings support the promise of this novel adoptive T cell therapy in patients with relapsed B-ALL. Disclosures: No relevant conflicts of interest to declare.

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Role of CAR-T cell therapy in B-cell acute lymphoblastic leukemia

memo - Magazine of European Medical Oncology ◽

10.1007/s12254-019-00541-8 ◽

2019 ◽

Vol 13 (1) ◽

pp. 36-42 ◽

Cited By ~ 3

Author(s):

Hildegard T. Greinix

Keyword(s):

T Cells ◽

Acute Lymphoblastic Leukemia ◽

T Cell ◽

B Cell ◽

Response Rate ◽

Lymphoblastic Leukemia ◽

Car T Cells ◽

Car T Cell ◽

Car T ◽

Cell Acute Lymphoblastic Leukemia

SummaryChimeric antigen receptor (CAR) T cells are genetically engineered cells containing fusion proteins combining an extracellular epitope-specific binding domain, a transmembrane and signaling domains of the T cell receptor. The CD19-CAR T cell product tisagenlecleucel has been approved by the US Food and Drug Administration and the European Medicines Agency for therapy of children and young adults under 25 years with relapsed/refractory B‑cell acute lymphoblastic leukemia (ALL) due to a high overall response rate of 81% at 3 months after therapy. The rates of event-free and overall survival were 50 and 76% at 12 months. Despite the high initial response rate with CD19-CAR‑T cells in B‑ALL, relapses occur in a significant fraction of patients. Current strategies to improve CAR‑T cell efficacy focus on improved persistence of CAR‑T cells in vivo, use of multispecific CARs to overcome immune escape and new CAR designs. The approved CAR‑T cell products are from autologous T cells generated on a custom-made basis with an inherent risk of production failure. For large scale clinical applications, universal CAR‑T cells serving as “off-the-shelf” agents would be of advantage. During recent years CAR‑T cells have been frequently used for bridging to allogeneic hematopoietic stem cell transplantation (HSCT) in patients with relapsed/refractory B‑ALL since we currently are not able to distinguish those CAR‑T cell induced CRs that will persist without further therapy from those that are likely to be short-lived. CAR‑T cells are clearly of benefit for treatment following relapse after allogeneic HSCT. Future improvements in CAR‑T cell constructs may allow longer term remissions without additional HSCT.

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