CAR T-cell therapies continue their progress to change cancer treatment paradigms.
CAR T Cells and solid tumors
Targeting solid tumors with CAR T Cells continues to be a formidable challenge and a far-reaching goal for the scientific community. ASCO 2019 brought a glimmer of hope from the next-generation CAR T Cells that combine more than one modality of action. Although the data comes from relatively-small, early-phase clinical trials, they indicate the great potential of such approaches outside the hematologic malignancies space. CAR T Cells’ ability to kill tumor cells can be overthrown by immunosuppressive interactions such as PD1/PD-L1. Blocking such interactions with the use of monoclonal antibodies targeting the PD1/PD-L1 axis could therefore augment the activity of CAR T Cells. Researchers are employing this strategy by either topping-up CAR T Cell therapies with an anti-PD1 monoclonal antibody (MAb) or by incorporating the MAb within the CAR T Cells to ensure conducive tumor microenvironment for optimal activity of the CAR T-Cell therapy.
Following on the trail set by CAR Ts targeting CD19—the ideal antigen expressed in most B-cell malignancies, the search is on for the holy grail: a promising CAR target in solid tumors. Mesothelin, a cell-surface antigen expressed by most solid tumors, is currently being tested as a potential such target. Data from a Phase I dose-escalation trial recruiting patients with heavily-pretreated mesothelin-expressing pleural cancers including malignant pleural mesothelioma (MPM) and metastatic breast and lung cancers, showed that mesothelin-targeted CAR T Cells intrapleurally administered were safe and yielded encouraging antitumor activity. Of the eighteen MPM patients treated with the CAR T Cells, fourteen received Keytruda as additional anti-PD1 therapy and in this subset, two patients showed a complete metabolic response, five showed PR, and four SD. Interestingly, no objective responses were observed prior to PD1 inhibition with Keytruda (abstract: 2511). These promising results not only suggest that mesothelin is a promising target, but they also indicate that combining CAR T Cells with PD1-blocking agents may find an application in solid tumors.
Two solid tumor types with great unmet need, gastric cancer and pancreatic adenocarcinoma, are also being targeted by CAR T-Cell therapy, this time directed at Claudin 18.2 (CLDN 18.2), a protein highly expressed in these malignancies. Data from a small Phase I study presented at ASCO 2019 showed that this approach was well tolerated and demonstrated encouraging clinical activity, with one out of eleven evaluable patients achieving CR, three achieving PR, and five experiencing SD (ORR rate of 33.3%). The mPFS was 130 days (abstract: 2509).
CAR T Cells continue to show promise in hematological malignancies
Celgene’s CD19-targeting lisocabtagene maraleucel (liso-cel) demonstrated encouraging efficacy in heavily pretreated Non-Hodgkin Lymphoma (NHL) patients. The TRANSCEND NHL 001 trial also identified a potential target patient subpopulation that may differentiate liso-cel from the FDA-approved, also CD19-targeting Kymriah and Yescarta. Data presented at ASCO 2019 showed that seven out of nine heavily-pretreated MCL patients responded to liso-cel treatment (78% ORR). Over half of the patients experienced grade 3/4 treatment-related adverse events. Cytokine release syndrome (CRS), a common and potentially serious adverse event connected to CAR T-Cell therapy, occurred in 33% of patients; however, it was grade 1 in all cases and was resolved, on average, within 6 days (abstract: 7516). These results can potentially demarcate liso-cel from Kymriah and Yescarta, which are yet to show any significant benefit in MCL patients. Another niche patient population where liso-cel showed efficacy is NHL patients with secondary CNS lymphoma, a patient group with a high unmet need. Data at ASCO 2019 showed that four out of nine evaluable patients with relapsed/refractory (R/R) B-cell NHL with secondary CNS lymphoma achieved CR, and the treatment had manageable toxicity, with one patient experiencing grade 2 CRS and another a grade 3 neurological event (abstract: 7515).
Given the current challenges (e.g., manufacturing logistics, high levels of toxicity, and reimbursement), CAR T-Cell therapy is still far from becoming a mainstream treatment practice. Nevertheless, the progress seen at ASCO 2019 indicates that not only are CAR T-Cells are here to stay, but that they have the incredible potential to change the treatment paradigm across multiple oncology indications.