Following the success of CAR-T-cell therapy for the treatment of B-cell acute lymphoblastic leukaemia (B-ALL), many investigators are currently designing strategies to obtain similarly successful results in the treatment of other haematological malignancies and solid tumours. Challenging aspects include the careful selection of target antigen, the management of 'on-target, off-tumour' toxicity, and the modulation of the immunosuppressive tumour microenvironment. The ongoing clinical trials and strategies that can increase the antitumour efficacy and safety of CAR-T-cell therapy are discussed by a group of researchers from the Memorial Sloan Kettering Cancer Center in a paper published recently in the Nature Reviews Clinical Oncology.
The engineered expression of chimeric antigen receptors (CARs) on the surface of T-cells enables the redirection of T-cell specificity. Early clinical trials using CAR-T-cells for the treatment of patients with cancer showed modest results, but the impressive outcomes of several trials of CD19-targeted CAR-T-cells in the treatment of patients with B-cell malignancies have generated an increased enthusiasm.
All CAR designs contain an antigen-recognition domain and a signalling domain that provides signal to activate T-cells. Only this signalling domain is present in first-generation CARs. However, a co-stimulatory signalling domain is added in second-generation CARs, and in third-generation CARs two co-stimulatory signalling domains are added.
The signalling domains stimulate T-cell proliferation, cytolysis and cytokine secretion to eliminate the target cell.
The patients' own T-cells (or those from an allogeneic donor) are isolated, activated and genetically modified to generate CAR-T-cells, which are then infused into the same patient. This approach carries a very low risk of graft-versus-host disease and enables lipid, protein and carbohydrate antigens to be targeted by T-cells in an MHC-unrestricted fashion. Additionally, one CAR design can be used to treat all cancers expressing the same antigen. The need to generate T-cells for each patient was once considered to be a financial and technical obstruction to this therapeutic approach, but the success of CAR-T-cell therapy for the treatment of B-ALL has demonstrated that CAR-T-cells can be produced efficiently and for a reasonable cost.
In the article, the authors discuss successful CD19-targeted CAR-T-cell therapies, CAR-T-cell designs targeting other molecules for the treatment of haematological malignancies, and novel targets proposed for the treatment of solid tumours. They limited discussion to approaches with registered clinical trials.
Clinical trials of CAR T-cell therapy for the treatment of cancer have mostly been conducted in patients with CD19-positive haematological diseases, such as B-ALL, chronic lymphocytic leukaemia, follicular lymphoma, diffuse large B-cell lymphoma, and mantle-cell lymphoma. Novel CAR targets are required for the effective treatment of patients with haematological malignancies that do not express CD19. A subset of patients treated with emergence of CD19-specific CAR-T-cells experience disease relapse with CD19-negative tumour escape variants. Examples of the most-promising CAR-T-cell targets for the treatment of haematological malignancies include: CD22, CD20, ROR1, and Igκ for the treatment of B-cell malignancies; BCMA and CD138 for plasma malignancies; and CD33, CD123 and LeY for myeloid malignancies.
Several researchers are investigating the use of CAR T-cell therapy for the treatment of solid tumours. These studies require the prior identification of new antigens and the development of preclinical models of solid tumour in which to characterize therapies based on these antigens. A second-generation CAR targeting prostate specific membrane antigen is investigated for the treatment of prostate cancer. Mesothelin-specific CAR-T-cells were investigated in a first-in-man clinical trial for patients with malignant pleural mesothelioma. Investigators plan to treat patients with mesothelioma using T-cells expressing a CAR targeted at fibroblast activation protein alpha. CARs specific for EGFR and EGFR variant receptors are undergoing clinical evaluation in patients with glioma. CEA-targeted CAR-T-cells are currently being tested to treat patients with adenocarcinoma liver metastases. CAR-T-cells targeted at the form of CD171 expressed on malignant cells are being investigated for the treatment of refractory or recurrent neuroblastoma. Tumours of neuro-ectodermal origin, including neuroblastoma, overexpress the disialoganglioside GD2; CAR-T-cells targeted at GD2 have been investigated in clinical trials. A third-generation glypican-3 specific CAR has been tested preclinically and will be investigated for clinical efficacy in patients with hepatocellular carcinoma. A clinical trial conducted to test third-generation HER2-specific CAR-T-cells in patients with metastatic cancers was terminated after a patient with colon cancer died of severe acute respiratory failure as a result of the treatment. Despite this severe toxicity, other trials with HER2-specific CAR-T-cells are planned in sarcoma and glioblastoma. First-generation CAR-T-cells targeted at IL-13Rα have been tested clinically in patients with glioblastoma.
Several approaches have been developed to improve the antitumour efficacy of CAR-T-cell therapy and they extend beyond the choice of a target antigen. In their article, the authors discuss the strategies that are currently being translated to the clinic:
- Engineered CAR-T-cells that secrete pro-inflammatory cytokines (armoured CAR-T-cells)
- Dual receptor expression to target tumour cells and convert tumour-derived cytokines into T-cell activators
- Using natural killer (NK)-cell-based recognition domains in CARs
- Combination therapy with monoclonal antibodies targeting immune-checkpoint inhibitory receptors to relieve immunosuppression
- Infusion of two populations of CAR-T-cells to eradicate B cells and enable increased persistence of tumour-specific CAR-T-cells by preventing antibody responses against their foreign antigen components
- Targeting the tumour vasculature with CAR-T-cells, such as VEGFR-2-specific CAR-T-cells.
The serious risk of toxicity associated with CAR-T-cell therapies is becoming increasingly apparent. One of the probable causes of cytokine-release syndrome (CRS) is the release of inflammatory cytokines produced by large numbers of activated CAR-T-cells.
The symptoms of CRS include hypotension, fevers, and reversible neurological complications, such as delirium and seizure-like activity.
Currently, most CRS toxicities are manageable with high-dose steroids, vasopressors, ventilatory support, and supportive care. An increase in IL-6 levels has been associated with severe CRS, and an anti-IL-6R antibody, tocilizumab, has been used in the clinic to dampen the effects of CRS in many patients, but this approach has not been effective in all cases of CRS.
A correlation has been found between the levels of C-reactive protein in serum and CRS severity. In addition, CRS severity can be associated with tumour burden at the time of treatment, which indicates that patients with lower tumour burden could have a reduced risk of severe CRS.
Jackson HJ, Rafiq S, Brentjens RJ. Driving CAR T-cells forward.Nature Reviews Clinical Oncology 2016; 13, 370–383. doi:10.1038/nrclinonc.2016.36