Multiple myeloma: Anti-BCMA BiTE AMG 701 shows preclinical promise

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Published: 8 Dec 2019
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Dr Yu-Tzu Tai - Dana-Farber Cancer Institute, Boston, USA

Dr Yu-Tzu Tai speaks to ecancer at the ASH 2019 meeting in Orlando about updated results from a study evaluating the anti-BCMA bispecific T-cell engager (BiTE) AMG 701 for multiple myeloma.

She reports that AMG 701 can potently induce myeloma cell lysis in sensitive and resistant cells.

Dr Tai also details that they found that AMG 701 significantly induces CD4 and CD8 T cell proliferation and activation.

ecancer's filming has been kindly supported by Amgen through the ecancer Global Foundation. ecancer is editorially independent and there is no influence over content.

Read more about the study here

Multiple myeloma: Anti-BCMA BiTE AMG 701 shows preclinical promise

Dr Yu-Tzu Tai - Dana-Farber Cancer Institute, Boston, USA

The abstract that I will share with you is AMG 701 preclinical studies in multiple myeloma. The reason why we are doing this study is because from our previous study we know that BCMA is a very specific target antigen in multiple myeloma. This study is not just our study, also coupled with other people’s studies that we know this target antigen is a very good, ideal, target antigen for immunotherapies in multiple myeloma.

The method we are using is called CAR T-cell systems, that’s where we incubate with multiple myeloma cells with T-cells, effector cells either from T-cells, enriched CD3 T-cells, or PBMC and follow the time-point we assay what is the capacity of AMG 701 to induce multiple myeloma cell lysis in the presence or absence of bone marrow stromal cells or osteoclasts. Both are two components, very important components, to protect myeloma cells in the bone marrow microenvironment and also play a very significant role to induce myeloma resistant to current therapies.

The results – we found that AMG 701 can potently induce myeloma cell lysis regardless of those factors that either I just mentioned – bone marrow stromal cells or osteoclasts – they can very significantly induce myeloma cell lysis, not just sensitive cells but also resistant cells. Especially we have the data demonstrating resistance to IMiDs, immunomodulatory drugs such as lenalidomide, pomalidomide or bortezomib. In addition, we also followed up the T-cell activation and proliferation and differentiation to see whether this AMG 701 can induce T-cell proliferation and differentiation in the presence of myeloma targeted cells. We found that it significantly induced T-cell differentiation activation and that is validated by cell proliferation assay specifically graded on the CD3 proliferative cells that we quantitate central memory and effector memory cell portions and we found that AMG 701 can induce EM and a CM subset of T-cells upon treatment and this is time dependent. There is a time dependency – at day 7 the induction is even higher. When we evaluate CD8 portion ratio to CD4 we also found that the CD8 increment is much more significant than CD4 which is supporting data since the CD8 subset of T-cells are the main killer cells to lyse the tumour.

Because this is a BiTE, bispecific T-cell engager, so it’s a little bit different from CAR T-cells. CAR T-cells are active so you transfect your vectors into the key cells and it’s not off the shelf. But AMG 701 is an off the shelf product so when you need it you can administer it and when you don’t want it you can just withdraw it. So in terms of toxicity perhaps this approach will be more feasible. In fact, the first BCMA BiTE that’s called AMG 420, although it has much poorer pharmacokinetics compared to AMG 701, the clinical trial, first in human clinical trial, has already shown a very impressive response rate – 70% response rate – in a very heavily pre-treated myeloma patient population that was just reported this year in ASCO and the IMW meeting in September. I think this is precedent and this is centre stage for us to evaluate this better, improved molecule because it contains an FC portion leading to a higher, longer half-life in the patient serum. We are hoping that this molecule can allow a once per week injection into the patient which will be much favourable.

Next for the study, I forgot to mention because we also have in vivo data to support to combine AMG 701 with immunomodulatory drugs, lenalidomide and pomalidomide. We just presented the data at ten o’clock that actually we have a very systematic approach that we demonstrate in the presence of lenalidomide, pomalidomide AMG 701 induced myeloma cell lysis is further enhanced and that can also overcome bone marrow stromal cells or osteoclast protective effects. In the in vivo model we further used suboptimal doses of AMG 701 in the presence or absence of lenalidomide and we observed under these conditions only the combination group can further regress tumour regrowth compared to the monotherapy alone group. So all those data provide further evidence or warrant future combination trials of combining AMG 701 with lenalidomide or pomalidomide which has already been standard care of therapy in multiple myeloma to further eradicate minimal residual diseases to prolong, extend, durability of such therapy and hopefully cure the disease. That’s what we all hope.