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CAR-T Meeting 2021 | CAR-T vs. BiTEs in B-cell malignancies

Marion Subklewe, MD, LMU Hospital Munich, Munich, Germany, compares CAR T-cells to bispecific T-cell engagers (BiTEs). Firstly, Prof. Subklewe highlights that there are no randomized trials in any disease comparing CAR T-cells to BiTEs. Different parameters can be compared between CAR T-cells and BiTEs, including construct design, manufacturing, and production time. Additionally, data from clinical trials can provide insights into aspects such as safety and efficacy. Compared to CAR-T therapies, the BiTE platform provides an off-the-shelf product with a high safety profile, which are significant advantages. In the future, predictive biomarkers are needed to stratify patients to the safest and most successful treatment option. This interview took place during the 3rd European CAR T-cell Meeting.

Transcript (edited for clarity)

My name is Marion Subklewe, and I had the T-cell bispecifics and CAR T-cell program at the LMU. I’m happy to give you a short summary on the pro and con session from the third CAR T-cell Meeting of EHA and EBMT. I had the position of pro T-cell bispecifics, and my counterpart was Catherine Thieblemont who gave a pro CAR-T talk, and we focused on the setting of B-cell malignancies.

Clearly, first of all, there’s no randomized trial in any entity comparing bispecifics to CAR T-cells, so the answer: pro BiTE or pro CAR T-cells cannot be answered in any disease entity...

My name is Marion Subklewe, and I had the T-cell bispecifics and CAR T-cell program at the LMU. I’m happy to give you a short summary on the pro and con session from the third CAR T-cell Meeting of EHA and EBMT. I had the position of pro T-cell bispecifics, and my counterpart was Catherine Thieblemont who gave a pro CAR-T talk, and we focused on the setting of B-cell malignancies.

Clearly, first of all, there’s no randomized trial in any entity comparing bispecifics to CAR T-cells, so the answer: pro BiTE or pro CAR T-cells cannot be answered in any disease entity. We can talk about parameters, and I like to highlight some that differ in principle like construct, design, manufacturing, and production time, and there’s also data from clinical trials, giving us hints on aspects like safety and efficacy.

First, I’d like to remind everybody that bispecifics rely on co-stimulation through the target cells, or it might be the clustering of multiple CD3 molecules in the immunological synapse, with the CAR T-cells provide their own co-stimulatory molecules; however, although this appears to be a clear weakness for T-cell activation, the bispecific setting, there’s also a lot of data that T-cell fitness prior to leukapheresis, and T-cell subset composition, and possible manipulation, green manufacturing impacts efficacy, and clearly, we see T-cell exhaustion after CAR T-cell transfusion. So I think the data supports the notion that T-cell fitness is highly relevant in the BiTEs setting or the bispecifics setting in any way but also in the CAR T-cell setting.

If we look at manufacturing and production, bispecifics are an off-the-shelf product for immediate use provide a stable, reliable product, whereas CAR T-cells are faced with the challenge of production failure in about 10% of the cases and out-of-spec products in about 10% of the cases. And then some trials, they are conflicting data. But in the ZUMA-9 trial, this was associated with a lower response rate and CAR T-cell expansion, so the downside of CAR T-cells, we have the vein-to-vein time. We have manufacturing challenges, leading to production failure and out-of-spec products of unknown significance.

And if we look at safety, comparing T-cell bispecifics and CAR T-cells, we observe a lower rate of CRS and ICANS using bispecifics and particularly with novel constructs given subcutaneous. Importantly, we do observe, besides the higher incidence of CRS and ICANS, also long-term cytopenias and immunosuppression after CAR T-cells in a significant proportion of patients with prolonged neutropenia and some cases has also reported by our group also at this EHA/EBMT Meeting. We see also long-term lymphopenia, hypogammaglobulinemia, and an increased rate of opportunistic infections. So this has to be taken into account in the CAR T-cells setting.

Last, looking at efficacy, we clearly, as I said, have no comparative data. In particularly, if one considers intent-to-treat analysis was the loss of patients, as I said, during the CAR T-cell pipeline and production, it is completely open if the data that is provided from the non-randomized trials are comparable, also if you think of the different patient cohorts treated, and clearly, also depending on the different disease entities; however, so far, the data that is provided implies that there’s a higher response rate after CAR T-cells particularly in the setting of relapsed/refractory ALL. But these were much younger patients with an average age of 11 compared to the blin data from the TOWER trial. It was an average age of 43 years olds, and we also have reports on higher response rates in the aggressive aggressive diffuse large cell B-cell lymphomas but also in follicular lymphoma using CAR T-cells versus bispecifics but clearly, as I said, different patients, different trial design, different read-out, often not intent-to-treat, and I think we clearly can conclude that the comparison is difficult due to the different scenarios and the rule not to compare different trials with different patients and design.

But I think we will eventually need a comparison, and we need to define biomarkers to decide which immunotherapy is safe and most successful for each individual patient and clearly which platform is most suitable in an individual or personal approach. I think what we conclude from all these trials… And there’s an increasing awareness that T-cell subset composition, T-cell fitness, is very important component for the success of T-cell bispecifics as well as CAR T-cells. So I will have to wait more data to conclude on this, and clearly at the moment, it’s amazing that we have two platforms that are evolving as new treatment options for our patients.

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