Relapse and Resistance to CAR-T Cells and Blinatumomab in Hematologic Malignancies

Jacoby, Elad

doi:10.2991/chi.d.190219.001

Cited by 18 publications

(11 citation statements)

References 68 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“… 32 , 33 This appears to be likely due to immune pressure from long-term persistence of immunostimulatory domain-containing CAR-Ts compared to BiTEs. 34 In contrast, there was no CD19 loss observed in patients refractory to blinatumomab, a BiTE targeting CD19 and CD3. 35 The approval of blinatumomab has validated the T-BsAb approach for targeting CD19 in certain subsets of B cell lymphomas, but safety concerns have limited its use beyond ALL.…”

Section: Discussionmentioning

confidence: 97%

TNB-486 induces potent tumor cell cytotoxicity coupled with low cytokine release in preclinical models of B-NHL

Malik-Chaudhry

Prabhakar

Ugamraj

et al. 2021

mAbs

View full text Add to dashboard Cite

The therapeutic potential of targeting CD19 in B cell malignancies has garnered attention in the past decade, resulting in the introduction of novel immunotherapy agents. Encouraging clinical data have been reported for T cell-based targeting agents, such as anti-CD19/CD3 bispecific T-cell engager blinatumomab and chimeric antigen receptor (CAR)-T therapies, for acute lymphoblastic leukemia and B cell non-Hodgkin lymphoma (B-NHL). However, clinical use of both blinatumomab and CAR-T therapies has been limited due to unfavorable pharmacokinetics (PK), significant toxicity associated with cytokine release syndrome and neurotoxicity, and manufacturing challenges. We present here a fully human CD19xCD3 bispecific antibody (TNB-486) for the treatment of B-NHL that could address the limitations of the current approved treatments. In the presence of CD19+ target cells and T cells, TNB-486 induces tumor cell lysis with minimal cytokine release, when compared to a positive control. In vivo , TNB-486 clears CD19+ tumor cells in immunocompromised mice in the presence of human peripheral blood mononuclear cells in multiple models. Additionally, the PK of TNB-486 in mice or cynomolgus monkeys is similar to conventional antibodies. This new T cell engaging bispecific antibody targeting CD19 represents a novel therapeutic that induces potent T cell-mediated tumor-cell cytotoxicity uncoupled from high levels of cytokine release, making it an attractive candidate for B-NHL therapy.

show abstract

Section: Discussionmentioning

confidence: 97%

TNB-486 induces potent tumor cell cytotoxicity coupled with low cytokine release in preclinical models of B-NHL

Malik-Chaudhry

Prabhakar

Ugamraj

et al. 2021

mAbs

View full text Add to dashboard Cite

show abstract

“…First is an immune escape where malignant cells lose expression of the antigen targeted by CAR T cells, and second is the loss of functional CAR T cells. CD19‐negative B‐ALL relapse has been reported in 10–20% of cases with both CD28 and 4‐1BB‐based CD19 CAR T therapies 39,40 . Similarly, decreased CD22 expression has been reported in relapsed cases after CD22 CAR T therapy 30 .…”

Section: Acute Lymphoblastic Leukaemiamentioning

confidence: 96%

The evolving role of allogeneic haematopoietic cell transplantation in the era of chimaeric antigen receptor T‐cell therapy

et al. 2021

View full text Add to dashboard Cite

Summary Chimaeric antigen receptor T‐cell (CAR T) therapy has revolutionized the management of many haematological malignancies. It is associated with impressive disease responses in relapsed or refractory high‐grade B‐cell non‐Hodgkin lymphoma (B‐NHL) and acute lymphoblastic leukaemia (B‐ALL) with durable remissions in a subset of patients. Historically, haematopoietic cell transplantation (HCT) has been the standard consolidation strategy for many of these patients who are now being treated with CAR T. Relapses are frequent after CD19 CAR T therapy in B‐ALL and consolidation with allogeneic HCT (allo‐HCT) may improve survival of patients with high‐risk disease. There appears to be a clear difference in B‐ALL outcomes between paediatric and adult patients, with the latter having a much higher risk of relapse after CAR T therapy. Late relapses are infrequent in patients with B‐NHL and consolidation with allo‐HCT may not be needed in patients who achieve a complete remission after CAR T therapy. Future registry‐based and prospective studies will hopefully provide the needed data in the future to risk‐stratify the recipients of CAR T therapy. Meanwhile, we provide guidance on patient selection and practical issues with performing allo‐HCT after CAR T therapy.

show abstract

“…By the end of 2016, four different ICB drugs were also approved for the treatment of lymphoma and melanoma, among other cancers. Although the success of CAR-T cell therapy against hematologic cancers is promising, the mechanisms associated with failures have been reported and are the subject of recent investigations [12]. Notably, many challenges remain to be addressed to improve response rates such as minimum effective CAR-T cell dose, selection of CAR-T subtypes, adverse effects management, combination of therapies, formation and maintenance of immunological memory, suppressive microenvironment, and patient specificity, to mention a few [13].…”

Section: Introductionmentioning

confidence: 99%

CARTmath—A Mathematical Model of CAR-T Immunotherapy in Preclinical Studies of Hematological Cancers

Barros

Paixão

Valli

et al. 2021

Cancers

View full text Add to dashboard Cite

Immunotherapy has gained great momentum with chimeric antigen receptor T cell (CAR-T) therapy, in which patient’s T lymphocytes are genetically manipulated to recognize tumor-specific antigens, increasing tumor elimination efficiency. In recent years, CAR-T cell immunotherapy for hematological malignancies achieved a great response rate in patients and is a very promising therapy for several other malignancies. Each new CAR design requires a preclinical proof-of-concept experiment using immunodeficient mouse models. The absence of a functional immune system in these mice makes them simple and suitable for use as mathematical models. In this work, we develop a three-population mathematical model to describe tumor response to CAR-T cell immunotherapy in immunodeficient mouse models, encompassing interactions between a non-solid tumor and CAR-T cells (effector and long-term memory). We account for several phenomena, such as tumor-induced immunosuppression, memory pool formation, and conversion of memory into effector CAR-T cells in the presence of new tumor cells. Individual donor and tumor specificities are considered uncertainties in the model parameters. Our model is able to reproduce several CAR-T cell immunotherapy scenarios, with different CAR receptors and tumor targets reported in the literature. We found that therapy effectiveness mostly depends on specific parameters such as the differentiation of effector to memory CAR-T cells, CAR-T cytotoxic capacity, tumor growth rate, and tumor-induced immunosuppression. In summary, our model can contribute to reducing and optimizing the number of in vivo experiments with in silico tests to select specific scenarios that could be tested in experimental research. Such an in silico laboratory is an easy-to-run open-source simulator, built on a Shiny R-based platform called CARTmath. It contains the results of this manuscript as examples and documentation. The developed model together with the CARTmath platform have potential use in assessing different CAR-T cell immunotherapy protocols and its associated efficacy, becoming an accessory for in silico trials.

show abstract

Relapse and Resistance to CAR-T Cells and Blinatumomab in Hematologic Malignancies

Cited by 18 publications

References 68 publications

TNB-486 induces potent tumor cell cytotoxicity coupled with low cytokine release in preclinical models of B-NHL

TNB-486 induces potent tumor cell cytotoxicity coupled with low cytokine release in preclinical models of B-NHL

The evolving role of allogeneic haematopoietic cell transplantation in the era of chimaeric antigen receptor T‐cell therapy

CARTmath—A Mathematical Model of CAR-T Immunotherapy in Preclinical Studies of Hematological Cancers

Contact Info

Product

Resources

About