Intracavitary ‘T4 immunotherapy’ of malignant mesothelioma using pan-ErbB re-targeted CAR T-cells

Abstract

Malignant mesothelioma remains an incurable cancer. We demonstrated that mesotheliomas expressed EGFR (79.2%), ErbB4 (49.0%) and HER2 (6.3%), but lacked ErbB3. At least one ErbB family member was expressed in 88% of tumors. To exploit ErbB dysregulation in this disease, patient T-cells were engineered by retroviral transduction to express a panErbB-targeted chimeric antigen receptor (CAR), co-expressed with a chimeric cytokine receptor that allows interleukin (IL)-4 mediated CAR T-cell proliferation. This combination is referred to as T4 immunotherapy. T-cells from mesothelioma patients were uniformly amenable to T4 genetic modification and expansion/enrichment thereafter using IL-4. Patient-derived T4 T-cells were activated upon contact with a panel of four mesothelioma cell lines, leading to cytotoxicity and cytokine release in all cases. Adoptive transfer of T4 immunotherapy to SCID Beige mice with an established bioluminescent LO68 mesothelioma xenograft was followed by regression or eradication of disease in all animals. Despite the established ability of T4 immunotherapy to elicit cytokine release syndrome in SCID Beige mice, therapy was very well tolerated. These findings provide a strong rationale for the clinical evaluation of intracavitary T4 immunotherapy to treat mesothelioma.

CAR T-cell immunotherapy of MET-expressing malignant mesothelioma

“…Analysis of a larger series of MPM that contained the subset presented here confirmed, as expected, that epithelioid tumors were associated with improved patient survival. 15 Expression of MET was detected by immunohistochemistry in 67.6% of MPM, either at low (28.1%), intermediate (24.6%) or high intensity (14.9%). Receptor distribution was cytoplasmic with membranous accentuation (Fig.…”

“…14 In keeping with this, we have recently demonstrated that ErbB re-targeted CAR T-cells achieve significant antitumor activity combined with excellent safety in pre-clinical models of malignant pleural mesothelioma (MPM). 15 The MET receptor tyrosine kinase is also aberrantly expressed in a large proportion of mesotheliomas [16][17][18][19][20][21] and has been proposed as an attractive therapeutic target in this disease. 18,22,23 Disappointingly however, a phase II trial of the selective MET inhibitor tivantinib has recently been terminated (https://clini caltrials.gov/ct2/show/NCT01861301; accessed March 25th, 2017).…”

Progress and challenges in Mesothelioma: From bench to bedside

“…These products are Major Histocompatibility Complex (MHC)-independent, meaning they can be utilised in diverse populations. Anti-mesothelin and anti-fibroblast activation protein (FAP; which is expressed ubiquitously in the MPM tumour microenvironment) CAR T-lymphocytes have both been shown to induce regression in MPM xenograft tumour models and can be delivered locally, to the pleura, using an indwelling pleural catheter [78,79]. Several Phase I studies testing the safety of these approaches are currently underway.…”

Advances in the use of natural receptor- or ligand-based chimeric antigen receptors (CARs) in haematologic malignancies

“…Amongst the CARs brought into the clinic (Table 1), the ligand-based CARs IL-13Rα and T1E are the ones with clinical information available [36, 46, 57–59]. …”