Dual CD19/22 Targeting CAR-T Therapy Plus Pembrolizumab Promising for DLBCL


Wendy Osborne, MBBS (Hons), MRCP, FRCPath, Consultant Hematologist, Freeman Hospital, Newcastle, United Kingdom, discusses results from the phase 1 Alexander study, which evaluated AUTO3, a CAR-T therapy targeting CD19/22 with limited duration of PD-1 blockade, in combination with pembrolizumab for patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL).


Hello. I'm Dr. Wendy Osborne. I'm a Consultant Hematologist from Newcastle in the UK. I want to summarize the data that has been presented from the Alexander study. The Alexander study is a phase 1/phase 2 study looking at AUTO3, a bicistronic CAR, in combination with pembrolizumab for patients with relapsed/refractory diffuse large B‑cell lymphoma.

We know that CD19 CARs are very effective in obtaining response for patients with relapsed lymphoma. However, the concerns are that often the responses aren't durable. About a third, just over a third of patients do go on and have a further relapse.

There are many possible mechanisms, but AUTO3 is designed to try and overcome 2 of the possible escape mechanisms. One is CD19 escape. Therefore, the CAR is designed as a CD19/22, so a bicistronic CAR, to try and by targeting two antigens try and prevent relapse for patients by CD19 escape.

The other mechanism where we're concerned that patients who have had CAR-T are relapsing is because of CAR-T exhaustion. It may be that with using pembrolizumab, a PD‑1 inhibitor, we can try and prevent or reduce CAR-T exhaustion and therefore allowing sustained responses.

It was a dose escalation design starting initially with 50 million cells and then moving up through to the final 450 million dose. Pembrolizumab was initially introduced on day 14 for safety to ensure that after peak CAR-T expansion, it was allowed to be introduced. Once we saw that the safety data were good, pembrolizumab was now and is now introduced into day ‑1 as part of the conditioning.

The safety data are really encouraging. 23 patients have been treated. There are no events of severe CRS. Most patients actually had just a grade 1 cytokine release syndrome. Only 17% of patients required tocilizumab. This is different from the experience we have with currently available CARs, where there's significant cytokine release and many patients have to go to intensive care.

In the 23 patients, there was only one neurotoxicity event as well. Actually, this was quite atypical. The patient had some facial weakness and one‑sided weakness. Actually, in the history, the patient had had a similar episode 10 years previously, so it may or may not be related to the CAR.

We also saw that with AUTO3, that no patients had neurotoxicity when it was used in combination with pembrolizumab and above 150 million cells. With this safety data, it's been encouraging. The recommended phase 2 dose going forward is the dose range of 150 to 450 million cells using pembrolizumab on day ‑1.

Now, when we look at the efficacy data, although it is early—we've only treated 23 patients—it is really encouraging. If we look at the complete response rate overall, it's 48 percent of patients who have obtained a complete response rate.

If we look at those patients who have had more than 150 million cells, i.e., the recommended phase 2 dose, the complete response rate is 56%. Again, although it's only small numbers, 8 patients have been treated with more than 150 million cells and day ‑1 pembrolizumab.

Their complete response rate is 63%. Early days but really encouraging in a product which appears to have minimal toxicity. These responses are durable. Out of the 23 patients, 11 have had a complete response. 10 out of the 11 have had a sustained response.

If we just focus in on the patients who would be moving through as the recommended dose, more than 150 million and day ‑1 pembrolizumab, that's nine out of nine. They have a sustained, complete response.

In summary, we have what appears to be a very safe product, so safe that we're now forward to outpatient‑based delivery for the expansion phase of this study, with minimal CRS, no severe CRS, and no events of neurotox at the dose that we are taking forward into the recommended phase 2 dose.

A safe product and the efficacy data look very encouraging when we compare that to the currently available data for current CAR-Ts. I was pleased to summarize the Alexander study for you. Thank you.

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