Dual-Targeting CAR T Cells Offers Hope to DLBCL Patients

Liam Davenport

June 15, 2020

A novel chimeric antigen receptor (CAR) T cell that targets two antigens at the same time could, in combination with an immune checkpoint inhibitor, be an effective strategy for treating patients with relapsed and refractory diffuse large B-cell lymphoma (DLBCL), suggests early trial data.

The research was presented at the 2020 annual meeting of the American Society of Clinical Oncology, held virtually because of the coronavirus pandemic.


The phase I/II ALEXANDER study involved AUTO3 (Autolus Therapeutics), the first bicistronic CAR T cell therapy targeting both CD19 and CD22.

It was given alone or in combination with the programmed death ligand 1 (PD-L1) inhibitor pembrolizumab (Keytruda, Merck) to 23 DLBCL patients who were refractory to chemotherapy or had relapsed.

The study, led by Dr Wendy Osborne, consultant haematologist at the Freeman Hospital, Newcastle upon Tyne, showed the treatment achieved a complete response in 56% of patients, with almost no instances of severe cytokine release syndrome or neurotoxicity.

The researchers say that, with AUTO3 achieving "impressive" durations of complete response and an "excellent" safety profile, the drug is being put forward for an outpatient expansion cohort, due to enrol soon.

'Important, Exciting'

Dr Michael Jain, Moffitt Cancer Center, Tampa, USA, told Medscape News UK that the researchers being able to manufacture the CAR T cell for all patients is "important".

He added that the "exciting thing about this therapy is that no patient had severe cytokine release syndrome, and only one patient had a grade 3 neurologic toxicity, so it seemed that the safety profile appears to be very good".

Dr Jain underlined, however, that the "goal of targeting two different targets instead of one is to try to have a better efficacy rate".

The admittedly "very short" follow-up has, however, so far only shown that "the overall response rate was in keeping with what we might expect" from CAR T cell therapies targeting CD19 alone.

'Quite Encouraging'

Study discussant Dr L Elizabeth Budde, City of Hope National Medical Center, Duarte, USA, commented that the key question with CAR T cells in DLBCL is whether clinicians can "dial down" the toxicities and "make it easier for patients" to undergo treatment, as well as improve its efficacy.

She said that the hypothesis in the ALEXANDER study is that immune "pressure" against two different antigens will "reduce the likelihood of tumour resistance" and improve both the response rate and durability of remission.

Dr Budde believes the response rate was "quite encouraging", despite the short follow-up, and that the safety profile compares "very favourably" with those seen in previous studies.

Consequently, she believes that, if the results can be reproduced in phase II studies and AUTO3 can be given on an outpatient basis, it will "bring CAR T cell therapy to a new level", and the drug "has the potential to be the best in class".

Presenting the findings, Dr Aravind Ramakrishnan, from Sarah Cannon Cell Therapy Program at St David's South Austin Medical Center, USA, said that currently available CAR T cells targeting CD19 are "highly active" in relapsed and refractory DLBCL.

However, only up to 37% of patients have a durable compete response, which may be due to "PD-L1 upregulation, leading to T-cell exhaustion, as well as CD19 antigen loss".

The aim with AUTO3 was therefore to target CD19 and CD22 simultaneously to "reduce the probability of antigen escape", with the addition of pembrolizumab to the pre-conditioning regimen "to prevent CAR T cell exhaustion".

Study Details

To examine its impact in DLBCL, the team conducted a single arm, open label phase I/II study in patients who were refractory to chemotherapy or who had relapsed after at least two lines of therapy or after autologous stem cell transplant.

The patients were started on a dose of 50 million CAR T cells, with escalation up to 150 million and 450 million cells. They received AUTO3 alone, or in combination with three doses of pembrolizumab starting on day 14, or with a single dose of the immune checkpoint inhibitor on day 1.

Twenty-three patients were enrolled. They had a median age of 55 years, ranging all the way up to 83 years, and 39% were female.

In terms of safety, grade ≥3 neutropenia was recorded in 81% of patients, while 63% had grade ≥3 anaemia and 56% grade ≥3 thrombocytopenia.

There were no cases of grade ≥3 cytokine release syndrome, and only one case of grade ≥3 neurotoxicity, which resolved rapidly with the use of steroids. No prophylactic measures were given for either complication.

Preliminary efficacy analysis indicated that the overall response rate across all dose levels was 65%, with 48% having a complete response. The longest durations of response have been with 50 and 150 million doses.

Dr Ramakrishnan described the longest response so far, in a 60-year-old man with bulky DLBCL who had refractory disease following three chemotherapy regimens.

After receiving the 50 million cell dose plus three doses of pembrolizumab from day 14, he had a complete response that has lasted for at least 18 months, with no cytokine release syndrome or neurotoxicity.

The study was funded by Autolus Therapeutics.

Dr Osborne reports: Honoraria - Kite Gilead; Pfizer Pharmaceuticals Israel; Roche; Takeda; Consulting or Advisory Role - Kite Gilead; MSD Brazil; Roche; SERVIER LABORATORIES LTD; Takeda Speakers' Bureau - Kite Gilead; MSD Brazil; Pfizer Pharmaceuticals Israel; Roche; Takeda; Travel, Accommodations, Expenses - Novartis pharma SAS.

Dr Ramakrishnan reports no relationships.

Dr Budde reports: Honoraria - AstraZeneca; Gilead Sciences; Kite/Gilead; Consulting or Advisory Role - Kite/Gilead; Roche/Genentech; Speakers' Bureau - AstraZeneca; Kite Pharma; Research Funding - Amgen; Merck; Mustang Bio; Travel, Accommodations, Expenses - AstraZeneca; Kite/Gilead; Roche/Genentech.

Dr Jain declares income for consultant and advisory work from: Kite/Gilead Sciences; Novartis.

ASCO 2020: Abstract 8001.


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