Immune cell engineering for cancer therapy

CAR T cell therapy is an effective cancer treatment, but biological and manufacturing hurdles hamper its broad breakthrough. Although the first step towards automated manufacture of CAR cells has been taken, new technologies are needed to enable the treatment of large patient groups.

CAR-T cell therapies targeting BCMA have shown promising responses in patients with multiple myeloma (MM), however primary resistance and relapse are frequently observed. Here the authors report the results of a phase I//II study of bispecific CAR T-cells targeting BCMA and CD19 in relapsed/refractory MM.

CAR T cell immunotherapy for paediatric solid and brain tumours is constrained by the availability of targetable antigens. Here, the authors investigate the landscape of cancer-specific exons as potential targets by analysing 1,532 RNAseq datasets from 16 types of paediatric solid and brain tumours.

Phenotype of cells in the infusion product as well at specific post-infusion time points has been associated with clinical response to CD19 CAR T cells. Here the authors present a single-cell multi-omics analysis of pre- and post-infusion CAR+ and CAR- T cells from patients with relapsed or refractory B-ALL or LBCL who received CD19 CAR T therapy.

The success rate of chimeric antigen receptor T cell therapy is high in blood cancers, yet individual patient characteristics might reduce therapeutic benefit. Here authors show that therapeutic response in multiple myeloma, acute lymphoblastic leukemia and non-Hodgkin lymphoma, and occurrence of severe cytokine release syndrome in multiple myeloma are associated with specific gut microbiome alterations.

Knight et al. assess short-term patient-reported outcomes (PROs) and markers of neurotoxicity in patients with leukaemia or lymphoma treated with LV20.19 CAR T cells. In this small trial cohort, the authors report improvements in mood following CAR T infusion and identify kynurenine pathway molecules as potential markers of mood and neurotoxicity.

Strategies to address the challenges associated with product manufacturing can improve chimeric antigen receptor (CAR) cell–based therapeutics. Here the authors report the results of two clinical trials in patients with B-cell malignancies, showing that place-of-care manufacturing has a low production failure rate with CD19-directed CAR-T cell products inducing high remission rates.

Natural killer (NK) cells are assessed for various therapies, but sub-optimal cryopreservation dampens their clinical feasibility. Here the authors show that pretreating human NK cells with IL-15/IL-18 prior to cryopreservation improves NK cell post-thaw viability and functions, potentially via anti-apoptosis gene induction and granzyme B degranulation.

It has been previously suggested that STING agonists can improve response to CAR-T therapy. Here the authors report the characterization of the STING agonist IMSA101, showing that STING-induced IL18 secretion enhances CAR-T activity in preclinical cancer models.

It has been suggested that targeting the PD-1/PD-L1 axis can increase the anti-tumor properties of chimeric antigen receptor (CAR)-T cells. Here the authors report that CAR affinity modulates the sensitivity of CAR-T cells to PD-1/PD-L1-mediated inhibition.

Alternatively activated macrophages have a pivotal role in resolving inflammation but in the tumour microenvironment they are immunosuppressive. Here author show that adoptively transferred engineered macrophages harbouring a heat-inducible genetic switch can resist the polarizing effect of the tumour microenvironment, and do not only remain pro-inflammatory themselves but also re-polarise the endogenous macrophages upon controlled warming with a purpose-made device.

A main challenge for the use of CAR-T in solid tumours is the identification of surface proteins as feasible targets. Here, the authors show TYRP1 as a target for CAR-T cell therapy in preclinical models of cutaneous, acral and uveal melanoma.

The subset of chronic lymphocytic leukemia (CLL) expressing the IGLV3- 21R110 BCR light chain often shows an aggressive clinical course. Here the authors report the development and characterization of IGLV3-21R110- targeted CAR T cells, showing selective targeting and eradication of IGLV3- 21R110 expressing CLL cells.

BCMA-specific CAR T-cell therapies have shown high response rates in multiple myeloma (MM), however the majority of patients still relapse. Here the authors show that CD24-positive MM cells increase after BCMA-CAR-T treatment in patients, and that dual-targeted BCMA/CD24 CAR-T cells can improve anti-tumor efficacy in MM preclinical models.

Human natural killer T (NKT) cells have been proposed as a cellular platform for CAR engineering. Here the authors report that IL-12 engineering reprograms CAR-expressing NKT cells to long-lived Th1-polarized cells with potent anti-tumor activity in leukemia and neuroblastoma preclinical models.