Chimeric antigen receptor (CAR) T-cell (CAR-T) therapy can provide durable remission in patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) after failure of chemoimmunotherapy. However, patients who are refractory or relapsing after CAR-T therapy have poor outcomes. Multiple mechanisms of CAR-T therapy failure have been proposed but management of these patients remains a challenge. As CAR-T therapy moves earlier in the treatment of DLBCL, we urgently need trials focused on patients with relapse after CAR-T therapy. Recent advances in novel immunotherapies such as bispecific antibodies, antibody-drug conjugates and next-generation CAR-T therapies may provide avenues for treatment. Here we review the available data on using these drugs after failure of CAR-T therapy and provide a framework for the ideal sequencing of these novel agents.
Recent studies have revealed the potential of tumor-infiltrating lymphocytes (TILs) to treat solid tumors effectively and safely. However, the translation of TIL therapy for patients is still hampered by non-standardized and laborious manufacturing procedures that are expensive and produce highly variable cellular products. To address these limitations, the CliniMACS Prodigy Tumor Reactive T cell (TRT) Process has been developed.
This study explores a novel therapeutic strategy for relapsed/refractory (R/R) Burkitt lymphoma (BL) by integrating autologous hematopoietic stem cell transplantation (ASCT) with tandem anti-CD19/CD22 chimeric antigen receptor (CAR) T cell therapy. A 20-year-old Asian male with refractory BL, whose lymphoma had not responded to multiple chemoimmunotherapy regimens, received myeloablative ASCT followed three days later by infusion of a novel third-generation CAR T cells engineered with CD28 and CD3ζ signaling domains, along with a TLR2 costimulatory domain. This resulted in sustained complete remission at the 306-day follow-up, without experiencing any severe complications.
Disease burden is a critical determinant of outcomes in CAR-T therapy for B-cell lymphomas, and one of the most widely used techniques for its assessment is Total Metabolic Tumor Volume (TMTV) measured via [F]FDG PET/CT. Biological parameters may further refine the risk profile. We analyzed baseline [F]FDG PET/CT scans from 40 patients treated with CAR-T, using an AI-based automated segmentation algorithm to determine TMTV.
Resistance to chimaeric antigen receptor (CAR) T cell therapy develops through multiple mechanisms, most notably antigen loss and tumour-induced immune suppression. It has been suggested that T cells expressing multiple CARs may overcome the resistance of tumours and that T cells expressing receptors that switch inhibitory immune-checkpoint signals into costimulatory signals may enhance the activity of the T cells in the tumour microenvironment. However, engineering multiple features into a single T cell product is difficult because of the transgene-packaging constraints of current gene-delivery vectors.
Chimeric antigen receptor T cell (CAR-T) therapy has proven successful for B cell lymphomas and leukaemias. This success has inspired the development of CAR-T for T cell malignancies. T cell lymphomas and T-ALL are highly heterogenous diseases but are united by poor prognosis in the relapsed/refractory (r/r) setting and the lack of any novel, targeted therapies.
