An Off-the-Shelf Drug to Rival CAR T Cells: 'Very Exciting'

Zosia Chustecka

December 07, 2019

ORLANDO, Florida — An investigational drug that can achieve the same results as complex cell therapy is creating a buzz here at the American Society of Hematology (ASH) meeting.

For the last few years, attention at this meeting has focused on the chimeric antigen receptor (CAR) T cells, mainly "because of their incredible efficacy," commented ASH Secretary Robert A. Brodsky, MD, professor of medicine and director of the division of hematology at Johns Hopkins School of Medicine in Baltimore, Maryland.

But new results with an off-the-shelf product are "very exciting" he said, because the drug can be given immediately and appears to achieve similar results.

The new product is mosunetuzumab (Genentech/Roche), a bispecific antibody that targets both CD3 (on the surface of T cells) and CD20 (on the surface of B cells). It works by redirecting T cells to engage and eliminate malignant B cells.

"The concept here is that this monoclonal antibody engages T cells and directs their cytotoxicity against B cells — it's basically an antibody using the patient's own T cells to do what a CAR T cell would do," Brodsky explained.

However, unlike CAR T cells, which are prepared for each individual patient in a complex process that involves genetic engineering that can take several weeks, mosunetuzumab is an off-the-shelf product that can be given to patients immediately (by intravenous infusion).

This is important, commented Brodsky, because very poor prognosis patients can deteriorate rapidly, and some may not survive while the CAR T cells are being made.

Clinical Trial Results

Stephen J. Schuster, MD

Clinical results come from a phase 1/1b trial (known as GO29781) conducted in 270 patients with poor-prognosis refractory/relapsed non-Hodgkin’s lymphoma. These patients had had previously been treated with a median of three therapies; in addition, 30 patients (11%) were resistant to or had relapsed after an initial response to CAR T-cell therapy, and 77 patients (29%) had progressed after a stem cell transplant.

"These patients had no available therapy that would be expected to improve survival," noted lead author Stephen J. Schuster, MD, of Abramson Cancer Center at the University of Pennsylvania in Philadelphia.

All patients received mosunetuzumab, with an initial treatment of eight cycles. Patients who achieved complete remission (CR) stopped therapy, while patients who had a partial response or had stable disease, continued treatment for 17 cycles.

Two thirds of patients (n = 180, 67%) had aggressive lymphomas, mainly diffuse large B-cell lymphoma (DLBCL; n = 117), while 85 patients (31%) had indolent disease, mainly follicular lymphoma (FL; n = 82). Objective responses were seen in 46 of 124 patients (37%) with aggressive lymphomas, and 24 (19%) of these patients achieved a CR.

Among patients with indolent lymphoma, objective responses were seen in 42 of 67 patients (63%) and 29 of 67 (43%) had CR.

The complete remissions appear to be long-lasting, Schuster commented. With a median follow-up of 6 months since achieving CR, 17 of 24 patients (71%) with aggressive lymphoma and 24 of 29 patients (83%) with indolent lymphomas remained free of disease.

"Some patients have remained in remission without additional therapy for more than a year," he commented.

In the subgroup of 30 patients who had previously received CAR T-cell therapy, the objective response rate was 38.9% and CR was achieved in four patients (22%). These rates are similar to what was seen in patients with aggressive lymphoma who had not previously received CAR T-cell therapy, Schuster commented.

He also noted that in some of these patients, molecular testing showed that the previously administered CAR T cells increased in number. This suggests that, in addition to its ability to kill cancerous B cells, mosunetuzumab may also help augment the effect of the prior CAR-T treatment.

Schuster also highlighted the results on re-treatment with mosunetuzumab. Patients who achieved CR stopped treatment — but if they relapsed, they were re-treated, and the responses seen on this retreatment were similar to those seen with initial treatment. "This is not seen with the CAR T cells," he noted.

Adverse events with mosunetuzumab were similar to those seen with CAR T cells, he noted, namely cytokine release syndrome, which was mostly mild and seen in 29% of patients; and neurological toxicity, which was moderately severe in 4% patients.

Overall, the results show that "mosunetuzumab generates long-lasting responses with a very tolerable safety profile in patients with B-cell non-Hodgkin lymphomas for whom multiple prior treatments have failed and whose prognosis is poor. Of particular interest, we are seeing durable complete remissions in patients whose lymphomas progressed after CAR T," Schuster commented in a statement.

Approached for comment, Peter Martin MD, chief of the Lymphoma Program at Weill Cornell Medicine and NewYork-Presbyterian, said he was excited to see these new data. "It's good news any time we find something with the potential to save lives."

"The more options that we have to offer to people lymphoma the better," he told Medscape Medical News. "There will always be scenarios where one approach might be better than another. I think there is a good chance that bispecific antibodies will have fairly broad approval in previously treated DLBCL. In many centers, it may be that bispecific antibodies are used most frequently post-CAR-T cells, while in other areas people who aren't candidates for CAR-T cells or can't receive them for whatever reason [could benefit from this new approach]." 

Laurie Sehn, MD, MPH, medical oncologist at the University of British Columbia in Vancouver, Canada, and chair of the Lymphoma Tumour Group, as well as an associate editor of ASH journal Blood, also commented for Medscape Medical News.

She agreed that the new data are exciting and noted that this abstract was chosen for the plenary session. She thought the data in the 30 patients who had already been treated with CAR-T cells was interesting. "This is a patient population with no other options that offer durable benefit, and mosunetuzumab clearly has clinical activity, with encouraging responses."

Sehn also noted that toxicity seen with the drug were "far less" than has been seen with CAR T cells, and the risk of high-grade CRS and neurological toxicity is "very low."

There are several other new products that are using this bispecific technology, she noted. One example is Regeneron's REGN1979, a bispecific antibody targeting CD20 and CD3, which is also being investigated in a clinical trial in relapsed/refractory B-cell non-Hodgkin's lymphoma, including in patients who were previously treated with CAR-T cells (abstract 762).

How Would it Be Used Clinically?

In response to a question from Medscape Medical News, Schuster suggested that initial use of mosunetuzumab would be in patients who have already tried CAR T-cell therapy and had either not responded or relapsed — in lymphoma, this is about two thirds of patients who are treated with this approach. This group of patients represents an unmet medical need, and this indication may be the quickest route to approval, he suggested.

Gary Schiller, MD, from UCLA Health, who moderated the press briefing agreed, and said this would be the quickest route to market, as it would need only a phase 2 clinical trial in this specific patient population. But this would likely be only the first use for this product, and then it could be expanded to a broader patient population, he added.

Another use would for mosunetuzumab would be to enhance CAR T-cell responses by redirecting the CAR T cell to other antigens without doing any additional gene editing, Schuster commented. The idea here is to "revive" previously administered CAR T cells that have stopped working, Schiller added.

This is a chemotherapy-free approach, Schuster emphasized. "In patients who have not had a lot of chemotherapy, you can see an increase in T cells," he commented.

Mosunetuzumab "stimulates and invigorates T cells," and it could be useful as a pre-treatment or a bridge to CAR T-cell therapy, he said.

So, the product could be used before CAR T-cell therapy, and equally it could be used after CAR T cell therapy, as it could boost responses in both cases.

"Larger, randomized trials are needed to further confirm these promising data and determine whether the treatment benefit of mosunetuzumab is enhanced when it is used earlier in the course of lymphoma therapy or in combination with other agents," he added.

Genentech says that mosunetuzumab and another bispecific antibody, CD20-TCB, are being evaluated in a robust clinical development program, both as a monotherapies and in combination with other therapies, in both aggressive and indolent non-Hodgkin's lymphoma.

Schuster reported relationships with Celgene, Genentech, Merck, Pharmacyclics, Acerta, AbbVie, Gilead, Nordic Nanovector, Pfizer, AstraZeneca, Loxo Oncology, and Novartis. Co-authors also have multiple disclosures, and several are employees of Genentech and Roche. Sehn consults with several pharmaceutics companies, including Verastem, Roche/Genentech, Morphosys, Takeda, Janssen, Lundbeck, Amgen, Teva, and Abbvie.

American Society of Hematology (ASH) 2019 Annual Meeting: Abstract 6. Presented December 8, 2019.

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