“T-cell Lymphoma and Secondary Primary Malignancy Risk After Commercial CAR T-cell Therapy” by Ghilardi et al
Nat Med (2024)
Abstract:
We report a T-cell lymphoma (TCL) occurring three months after anti-CD19 chimeric antigen receptor (CAR) T-cell immunotherapy for non-Hodgkin B-cell lymphoma. The TCL was diagnosed from a thoracic lymph node upon surgery for lung cancer. The TCL exhibited CD8+ cytotoxic phenotype and a JAK3 variant, while the CAR transgene was very low. The T-cell clone was identified at low levels in the blood before CART infusion and in the lung cancer. To assess the overall risk of secondary primary malignancy (SPM) after commercial CART (CD19, BCMA), we analyzed 449 patients treated at the University of Pennsylvania. At a median follow-up of 10.3 months, 16 patients (3.6%) had SPM. Median onset time was 26.4 and 9.7 months for solid and hematological malignancies, respectively. The projected 5-year cumulative incidence is 15.2% for solid and 2.3% for hematological malignancies. Overall, one case of TCL was observed, suggesting a low risk of TCL post-CART.
Why this matters:
The potential, albeit very rare, occurrence of secondary T cell neoplasms and their potential link to CAR T-cell therapy application has been major news in the past months. In one of the very first detailed public case reports, the authors outline the complexity of assessment, including causality assessment, both of which will be of major importance to the field in the years to come.
“Dictionary of immune responses to cytokines at single-cell resolution” by Cui et al
Nature (2023)
Abstract:
Cytokines mediate cell–cell communication in the immune system and represent important therapeutic targets. A myriad of studies have highlighted their central role in immune function, yet we lack a global view of the cellular responses of each immune cell type to each cytokine. To address this gap, we created the Immune Dictionary, a compendium of single-cell transcriptomic profiles of more than 17 immune cell types in response to each of 86 cytokines (>1,400 cytokine–cell type combinations) in mouse lymph nodes in vivo. A cytokine-centric view of the dictionary revealed that most cytokines induce highly cell-type-specific responses. For example, the inflammatory cytokine interleukin-1β induces distinct gene programmes in almost every cell type. A cell-type-centric view of the dictionary identified more than 66 cytokine-driven cellular polarization states across immune cell types, including previously uncharacterized states such as an interleukin-18-induced polyfunctional natural killer cell state. Based on this dictionary, we developed companion software, Immune Response Enrichment Analysis, for assessing cytokine activities and immune cell polarization from gene expression data, and applied it to reveal cytokine networks in tumours following immune checkpoint blockade therapy. Our dictionary generates new hypotheses for cytokine functions, illuminates pleiotropic effects of cytokines, expands our knowledge of activation states of each immune cell type, and provides a framework to deduce the roles of specific cytokines and cell–cell communication networks in any immune response.
Why this matters:
Cell to cell communication is complex. The authors provide the first comprehensive map of such cytokine-driven communication and networks, which may serve as an enormous resource when trying to understand the roots of immunity.
“CLDN6-specific CAR-T cells plus amplifying RNA vaccine in relapsed or refractory solid tumors: the phase 1 BNT211-01 trial” by Mackensen et al
Nat Med (2023)
Abstract:
The oncofetal antigen Claudin 6 (CLDN6) is highly and specifically expressed in many solid tumors, and could be a promising treatment target. We report dose escalation results from the ongoing phase 1/2 BNT211-01 trial evaluating the safety and feasibility of chimeric antigen receptor (CAR) T cells targeting the CLDN6 with or without a CAR-T cell-amplifying RNA vaccine (CARVac) at two dose levels (DLs) in relapsed/refractory CLDN6-positive solid tumors. The primary endpoints were safety and tolerability, maximum tolerated dose and recommended phase 2 dose (RP2D). Secondary endpoints included objective response rate (ORR) and disease control rate. We observed manageable toxicity, with 10 out of 22 patients (46%) experiencing cytokine release syndrome including one grade 3 event and 1 out of 22 (5%) with grade 1 immune effector cell-associated neurotoxicity syndrome. Dose-limiting toxicities occurred in two patients at the higher DL, resolving without sequelae. CAR-T cell engraftment was robust, and the addition of CARVac was well tolerated. The unconfirmed ORR in 21 evaluable patients was 33% (7 of 21), including one complete response. The disease control rate was 67% (14 of 21), with stable disease in seven patients. Patients with germ cell tumors treated at the higher DL exhibited the highest response rate (ORR 57% (4 of 7)). The maximum tolerated dose and RP2D were not established as the trial has been amended to utilize an automated manufacturing process. A repeat of the dose escalation is ongoing and will identify a RP2D for pivotal trials. ClinicalTrials.gov Identifier: NCT04503278.
Why this matters:
CARs are on the move beyond hematology but no one knows when and where. Andreas Mackensen and colleagues report on potential activity of mRNA boosted CAR T cells against Claudin 6 as a way of keeping activity alive for patient benefit.
“CD19-targeted CAR T cells in refractory antisynthetase syndrome” by Müller et al
Lancet (2023)
Introduction:
Idiopathic inflammatory myopathies are a group of rare, immune-mediated diseases that primarily affect the skeletal muscle but can also involve other organs such as the lungs, skin, and joints. Antisynthetase syndrome comprises a major cluster of such diseases and is characterised by the development of adaptive immune responses against various tRNA synthetases, including those for histidine (forming anti-Jo-1 antibodies), tyrosine (anti-PL7), alanine (anti-PL12), glycine (anti-EJ), isoleucine (anti-OJ), asparagine (anti-KS), phenylalanine (anti-Zo), and threonine (anti-HA). Histopathology studies of patients with antisynthetase syndrome have shown the presence of B cells and plasmablasts located adjacent to T cells in the affected muscles, and the condition is also associated with changes in the profile of peripheral B cells. In accordance with these findings, B-cell-depleting therapy with rituximab was efficacious in a subset of patients with antisynthetase syndrome, supporting the pathogenic role of autoreactive B cells. Antisynthetase syndrome can be refractory despite several treatment options—including glucocorticoids, intravenous immunoglobulins, T-cell-targeting drugs, and B-cell-targeting drugs—and is therefore associated with increased mortality.
Considering the pathophysiology of antisynthetase syndrome, treatment with chimeric antigen receptor (CAR) T cells that recognise CD19⁺ B cells might be useful in refractory forms of the disease. In the past 2 years, CAR T cells have been successful in the treatment of autoimmune diseases such as refractory systemic lupus erythematosus. Here we report the case of a patient with an idiopathic inflammatory myopathy who was successfully treated with CD19 CAR T cells.
Why this matters:
CARs are also entering non-malignant space based on their profound B cell depleting abilities. Fabian Müller et al report on the treatment of a patient with antisynthetase syndrome refractory to treatment, potentially cured by CD19-targeted CAR T cells, highlighting potential avenues of further development.