CAR-T and Ibrutinib: Better Together?

The following article features coverage from the American Society of Hematology (ASH) 2018 meeting. Click here to read more of Cancer Therapy Advisor‘s conference coverage.

SAN DIEGO — Based on some “preclinical evidence of synergy” between the anti-CD19 chimeric antigen receptor T-cell therapy (CAR-T) CTL019 and ibrutinib, researchers from the University of Pennsylvania, Philadelphia; Novartis; and the Parker Institute for Cancer Immunotherapy, among other institutions, paired the 2 medications together with the goal of testing the hypothesis that pretreatment and concurrent treatment would boost the complete remission (CR) rate seen in chronic lymphocytic leukemia (CLL).

During a presentation covering the results of the small pilot study at the 2018 American Society of Hematology (ASH) Annual Meeting and Exposition in San Diego, California,¹ Saar Gill, MD, PhD, University of Pennsylvania, Philadelphia, reported that the duo together “results in a high rate of sustained responses” and high rates of minimal residual disease-negative marrow response in patients with CLL.

Although CAR-T alone has the potential to spark CR in some cases of CLL, the outcome is not guaranteed, wrote the researchers in their abstract — and this prompted them to start searching for ways to also ensure remission remains durable.

For the study, the investigators enrolled 20 patients with CLL/SLL who were not in CR even after undergoing 6 months of treatment with ibrutinib. Investigators planned infusions for 19 of the study participants of 1-5×10⁸ CTL119 cells dosed as 10%, 30%, and 60% of the total planned dose over 3 days, provided that no problems arose after a patient received their first dose.

To manufacture CTL119, T cells were transduced (using lentiviral vectors) “to express a CAR comprising CD3z, 4-1BB, and humanized anti-CD19 scFv (CTL119).” Following lymphodepleting chemotherapy, the product was further prepared.

Once made, the median number of modified CAR-T cells given back to the patient was 5.3 × 10⁶/kg (range, 2.0-7.5). On days 7 through 10, there was a massive expansion of CAR-positive alleles, and by day 28, most of the CAR-T was not active, “reflecting eradication of antigen,” noted Dr Gill.

At 3 months, iwCLL was 6 CR, 4 PR, 3 SD, and 1 PD; 17 of 18 patients had morphologic CR, and 15 of 17 had flow-negative MRD CR, confirmed by flow cytometry. At 12 months, 10 of 11 patients had bone marrow remission, exhibiting CRs. Two of 7 patients maintained a CR, while 17 of 19 patients had adverse prognostic biomarkers.

Of 3 patients previously treated with CTL019, 2 were in MRD+ CR and 1 was refractory at 12 months.

As of July 16, 2018, 18 of 19 (95%) patients were still alive. However, 18 of the 19 patients who received the CAR-T experienced cytokine release syndrome, but none of the cases were grade 5 or fatal. One patient died due to cardiac arrhythmia in the setting of grade 4 neurotoxicity.

When an audience member asked for Dr Gill’s hypothesis about why cardiac toxicity in the single patient occurred, Dr Gill explained that it is well known that ibrutinib is associated with cardiac side effects. But, he added, the patient in question had a prior history of ischemic heart disease, and had not been administered ibrutinib for a few days because he had been intubated prior to that. The patient had also been given a drug for agitation; the drug is also known to be associated with cardiac arrest.

Another ASH attendee asked Dr Gill to speculate if the “119” aspect of the group’s humanized CAR had anything to do with the higher efficacy and lower-grade CRS. Dr Gill replied: “I speculate that the answer is ‘no’, but in truth, there are too many variables that are different between this study and earlier studies — the scFv [single-chain variable fragment] is different, otherwise manufacturing is reasonably similar … I suspect there are differences in the tumor mass burden between earlier studies and this study (this one being lower [burden]).”

“In patients not achieving CR despite at least 6 months of ibrutinib who were treated with humanized CART19, we found an iwCLL CR rate of 43% and at 3 months, there was a high bone marrow remission rate, including a 78% MRD negative response by deep sequencing,” Dr Gill noted. “This compares favorably to prior CART19 cell studies in patients with progressive CLL (iwCLL CR rates of 21% to 29%).”

Disclosure: This study was funded by Novartis. For a full list of disclosures, please refer to the original abstract.

Read more of Cancer Therapy Advisor‘s coverage of the ASH 2018 meeting by visiting the conference page.

Reference

1. Gill SI, Vides V, Frey NV, et al. Prospective clinical trial of anti-CD19 CAR T cells in combination with ibrutinib for the treatment of chronic lymphocytic leukemia shows high response rate. Oral presentation at: American Society of Hematology 60th Annual Meeting & Exposition; December 1-4, 2018; San Diego, CA. Abstract 298.