CAR‐T TREK through the lymphoma universe, to boldly go where no other therapy has gone before

Abstract

Chimeric antigen receptor (CAR) T cells (CART) therapies have changed and continue to change the treatment paradigms for B-cell malignancies because they can achieve durable complete remission in patients in whom multiple lines of treatment have failed. These unprecedented results have led to the widespread use of anti-CD19 CART therapy for patients with relapsed and refractory aggressive large B-cell lymphomas. While long-term follow-up data show that about one-third of patients achieve prolonged complete remission and are potentially cured, the majority of patients either do not respond to CD19 CART therapy or eventually relapse after CD19 CART therapy. These results are, on the one hand, driving intense research into identifying mechanisms of relapse and, on the other hand, inspiring the development of novel strategies to overcome resistance. This review summarizes current clinical outcomes of CART immunotherapy in B-cell non-Hodgkin lymphomas, describes the most upto-date understanding of mechanisms of relapse and discusses novel strategies to address resistance to CART therapy. We are indeed at the beginning of a scientific trek to explore the mechanisms of resistance, seek out new, more effective treatment approaches based on these discoveries and to boldly go where no other therapy has gone before!

Effects of the COVID-19 pandemic on publication landscape in chimeric antigen receptor-modified immune cell research

“…An interesting observation can be made regarding the role of co-stimulatory domains in these death rates. Preclinical studies have consistently shown that 4-1BB is safer than CD28 9 . However, the death rate is higher in Kymirah, which contains 4-1BB, than Yescarta, which contains CD28.…”

A serious challenge in fighting the COVID 19 pandemic: SARS CoV 2 vaccines in oncologic patients

“…In particular patients with B-cell malignancies are commonly treated with anti-CD20 monoclonal antibodies, resulting in prolonged lymphopenia and impairment to generate serological immunity against COVID-19 vaccine (13)(14)(15)(16)(17)(18)(19)(20). Of note, CD19and BCMA-targeted immunotherapies, including bispecific antibodies, CART and antibodies specifically ablate B-cells and plasma cells (21,22) and could therefore potentially severely affect the response of hematological patients to COVID-19 vaccines. Other drugs used in liquid cancers, especially BTK inhibitors, such as ibrutinib, and venetoclax are associated with failure to respond to COVID-19 vaccine (13,(15)(16)(17).…”

Born to survive: how cancer cells resist CAR T cell therapy

“…Despite this progress, a significant portion of patients still experience primary or secondary resistance to this treatment [ 1 ]. Resistance mechanisms to CAR T cell immunotherapy can involve the CAR T cells, the tumor microenvironment, or the cancer cells (Table 1 ) [ 2 ]. The current review focuses on cancer cells’ intrinsic mechanisms of resistance to CAR T cells therapy, which include loss of the target antigen (Ag), expression of inhibitory receptors, lack of costimulatory ligands, and resistance to immune killing (Figs.…”