Regional delivery of mesothelin-targeted CAR T cell therapy generates potent and long-lasting CD4-dependent tumor immunity

Abstract

Translating the recent success of chimeric antigen receptor (CAR) T cell therapy for hematological malignancies to solid tumors will necessitate overcoming several obstacles, including inefficient T cell tumor infiltration and insufficient functional persistence. Taking advantage of an orthotopic model that faithfully mimics human pleural malignancy, we evaluated two routes of administration of mesothelin-targeted T cells using the M28z CAR. We found that intra-pleurally administered CAR T cells vastly out-performed systemically infused T cells, requiring 30-fold fewer M28z T cells to induce long-term complete remissions. Following intrapleural T cell administration, prompt in vivo antigen-induced T cell activation allowed robust CAR T cell expansion and effector differentiation, resulting in enhanced anti-tumor efficacy and functional T cell persistence for 200 days. Regional T cell administration also promoted efficient elimination of extrathoracic tumor sites. This therapeutic efficacy was dependent on early CD4+ T cell activation associated with a higher intra-tumoral CD4/CD8 cell ratios and CD28-dependent CD4+ T cell-mediated cytotoxicity. In contrast, intravenously delivered CAR T cells, even when accumulated at equivalent numbers in the pleural tumor, did not achieve comparable activation, tumor eradication or persistence. The remarkable ability of intrapleurally administered T cells to circulate and persist supports the concept of delivering optimal CAR T cell therapy through “regional distribution centers.” Based on these results, we are opening a phase I clinical trial to evaluate the safety of intrapleural administration of mesothelin-targeted CAR T cells in patients with primary or secondary pleural malignancies.

Targeting the adenosine 2A receptor enhances chimeric antigen receptor T cell efficacy

“…This is potentially important given the previous reports indicating that CD4 + CAR T cells can significantly enhance overall CAR T cell efficacy (53)(54)(55). Hence, targeting A 2A R may enhance CAR T cell activity in part through augmenting CD4 + CAR T cell responses.…”

Syngeneic Syrian hamster tumors feature tumor-infiltrating lymphocytes allowing adoptive cell therapy enhanced by oncolytic adenovirus in a replication permissive setting

“…With regard to weaknesses of the model, key laboratory reagents are lacking and the growth of tumors over 2 weeks do not recapitulate the complexity which develops over a decade or more in human patients. Additionally, the route of administration of TIL in our study (intratumoral) was not typical of current TIL protocols that often employ intravenous administration, although also intratumoral 45 and intracavitary 46 have been used. Unfortunately, since a stimulatory hamster anti-CD3 antibody is lacking, a true REP growth step could not be performed, which limited the available options to local injection.…”

Medical treatment of malignant pleural mesothelioma relapses

“…However, nintedanib and bevacizumab are giving interesting results in the first line setting (6,32). Similarly, anti-mesothelin antibodies are under investigation in treatment naïve patients (33).…”