CAR T-Cell Therapy in Hematological Malignancies

Haslauer, Theresa; Greil, Richard; Zaborsky, Nadja; Geisberger, Roland

doi:10.3390/ijms22168996

Cited by 112 publications

(60 citation statements)

References 82 publications

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“…In our study, three partially responsive patients eventually experienced disease progression and died. Target antigen loss is an important mechanism of relapse or progression after CAR T cell immunotherapy ( 33 , 34 ). Liu et al.…”

Section: Discussionmentioning

confidence: 99%

Chimeric Antigen Receptor-Modified T Cell Immunotherapy for Relapsed and Refractory Adult Burkitt Lymphoma

Wu¹,

Cao²,

Zhang³

et al. 2022

Front. Immunol.

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Patients with Burkitt lymphoma who are refractory to initial therapy or who relapse after undergoing intensive chemotherapy and autologous stem cell transplantation (ASCT) usually have a poor prognosis. While there has been considerable progress in the use of chimeric antigen receptor-modified (CAR) T cell immunotherapy for the treatment of relapsed and refractory (r/r) malignancies, explicit data on adult patients with r/r Burkitt lymphoma are limited. We conducted two single-arm clinical trials to evaluate the clinical efficacy and toxicity of CD19/CD22 CAR T cell immunotherapy both alone (trial A) and in combination with ASCT (trial B) in adult patients with r/r Burkitt lymphoma. In total, 28 adult patients with r/r Burkitt lymphoma were enrolled [trial A (n = 15) and trial B (n = 13)]. The median doses of CD22 and CD19 CAR T cell infusions were 4.1 × 106/kg and 4.0 × 106/kg, respectively. Subsequently, after CAR T cell infusion, overall and complete responses were observed in 19 (67.9%) and 16 (57.1%) patients, respectively. The cumulative incidence rates of grade 2–4 cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome were 39.3% (11/28) and 10.7% (3/28), respectively. After a median follow-up duration of 12.5 months, 16 patients (5 in trial A and 11 in trial B) survived. Both the estimated 1-year progression-free and overall survival rates were 55.6%. Our preliminary results indicated that salvage therapy with CD19/CD22 CAR T cell infusion alone and that in combination with ASCT are effective in treating some adult patients with r/r Burkitt lymphoma.

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Section: Discussionmentioning

confidence: 99%

Chimeric Antigen Receptor-Modified T Cell Immunotherapy for Relapsed and Refractory Adult Burkitt Lymphoma

Wu¹,

Cao²,

Zhang³

et al. 2022

Front. Immunol.

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“…Cell therapies are rapidly becoming a new pillar of cancer treatment. Expansion and infusion of tumor-infiltrating lymphocytes resulted in notable clinical efficacy in melanoma patients [ 9 ], and chimeric antigen receptor T (CAR-T) cell therapy, in which a patient’s T cells are genetically engineered to express a synthetic CAR linking a cancer-targeting domain to T cell stimulatory domains, has transformed the treatment of hematological malignancies, as evidenced by five FDA-approved CAR-T cell products for B cell cancers [ 10 , 11 ]. CAR-T cells have yet to achieve widespread success in combating solid tumors, including ovarian cancers [ 12 ].…”

Section: Introductionmentioning

confidence: 99%

Minimally Invasive Preclinical Monitoring of the Peritoneal Cavity Tumor Microenvironment

Dunn

et al. 2022

Cancers

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Intraperitoneal (i.p.) experimental models in mice can recapitulate the process of i.p. dissemination in abdominal cancers and may help uncover critical information about future successful clinical treatments. i.p. cellular composition is studied in preclinical models addressing a wide spectrum of other pathophysiological states such as liver cirrhosis, infectious disease, autoimmunity, and aging. The peritoneal cavity is a multifaceted microenvironment that contains various immune cell populations, including T, B, NK, and various myeloid cells, such as macrophages. Analysis of the peritoneal cavity is often obtained by euthanizing mice and performing terminal peritoneal lavage. This procedure inhibits continuous monitoring of the peritoneal cavity in a single mouse and necessitates the usage of more mice to assess the cavity at multiple timepoints, increasing the cost, time, and variability of i.p. studies. Here, we present a simple, novel method termed in vivo intraperitoneal lavage (IVIPL) for the minimally invasive monitoring of cells in the peritoneal cavity of mice. In this proof-of-concept, IVIPL provided real-time insights into the i.p. tumor microenvironment for the development and study of ovarian cancer therapies. Specifically, we studied CAR-T cell therapy in a human high-grade serous ovarian cancer (HGSOC) xenograft mouse model, and we studied the immune composition of the i.p. tumor microenvironment (TME) in a mouse HGSOC syngeneic model.

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“…ACT has evolved from bench-to-bedside due to an increased understanding of tumor biology and general immunological principles [ 3 , 5 , 6 ]. The introduction of chimeric antigen receptor (CAR) technology has enabled the adoptive transfer of immune cells to become a more practical approach [ 7 , 8 ]. To date, T cells have been the most commonly engineered cell type, especially by CAR [ 7 ] and the current developments in CAR T cell-based therapies have greatly improved the scope of modern, targeted cancer therapy [ 9 ].…”

Section: Introductionmentioning

confidence: 99%

“…The introduction of chimeric antigen receptor (CAR) technology has enabled the adoptive transfer of immune cells to become a more practical approach [ 7 , 8 ]. To date, T cells have been the most commonly engineered cell type, especially by CAR [ 7 ] and the current developments in CAR T cell-based therapies have greatly improved the scope of modern, targeted cancer therapy [ 9 ]. Among others, the US Food and Drug Administration (FDA) has approved several CD19-directed CAR T cell therapeutic products for the treatment of hematological malignancies, such as types of B cell lymphomas and acute lymphoblastic leukemia (ALL) [ 7 ].…”

Section: Introductionmentioning

confidence: 99%

“…To date, T cells have been the most commonly engineered cell type, especially by CAR [ 7 ] and the current developments in CAR T cell-based therapies have greatly improved the scope of modern, targeted cancer therapy [ 9 ]. Among others, the US Food and Drug Administration (FDA) has approved several CD19-directed CAR T cell therapeutic products for the treatment of hematological malignancies, such as types of B cell lymphomas and acute lymphoblastic leukemia (ALL) [ 7 ]. In 2021, B cell maturation antigen (BCMA)-directed CAR T cells were approved for treating multiple myeloma (MM) [ 10 ].…”

Section: Introductionmentioning

confidence: 99%

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NK Cells Armed with Chimeric Antigen Receptors (CAR): Roadblocks to Successful Development

Dezfouli

Yazdi

Pockley

et al. 2021

Cells

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In recent years, cell-based immunotherapies have demonstrated promising results in the treatment of cancer. Chimeric antigen receptors (CARs) arm effector cells with a weapon for targeting tumor antigens, licensing engineered cells to recognize and kill cancer cells. The quality of the CAR-antigen interaction strongly depends on the selected tumor antigen and its expression density on cancer cells. CD19 CAR-engineered T cells approved by the Food and Drug Administration have been most frequently applied in the treatment of hematological malignancies. Clinical challenges in their application primarily include cytokine release syndrome, neurological symptoms, severe inflammatory responses, and/or other off-target effects most likely mediated by cytotoxic T cells. As a consequence, there remains a significant medical need for more potent technology platforms leveraging cell-based approaches with enhanced safety profiles. A promising population that has been advanced is the natural killer (NK) cell, which can also be engineered with CARs. NK cells which belong to the innate arm of the immune system recognize and kill virally infected cells as well as (stressed) cancer cells in a major histocompatibility complex I independent manner. NK cells play an important role in the host’s immune defense against cancer due to their specialized lytic mechanisms which include death receptor (i.e., Fas)/death receptor ligand (i.e., Fas ligand) and granzyme B/perforin-mediated apoptosis, and antibody-dependent cellular cytotoxicity, as well as their immunoregulatory potential via cytokine/chemokine release. To develop and implement a highly effective CAR NK cell-based therapy with low side effects, the following three principles which are specifically addressed in this review have to be considered: unique target selection, well-designed CAR, and optimized gene delivery.

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CAR T-Cell Therapy in Hematological Malignancies

Cited by 112 publications

References 82 publications

Chimeric Antigen Receptor-Modified T Cell Immunotherapy for Relapsed and Refractory Adult Burkitt Lymphoma

Chimeric Antigen Receptor-Modified T Cell Immunotherapy for Relapsed and Refractory Adult Burkitt Lymphoma

Minimally Invasive Preclinical Monitoring of the Peritoneal Cavity Tumor Microenvironment

NK Cells Armed with Chimeric Antigen Receptors (CAR): Roadblocks to Successful Development

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