Innovations in DLBCL: Antibody-drug conjugates, bispecific antibodies, CRISPR-edited CAR-T
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The advent of novel therapies has propelled, and continues to propel, tremendous progress and innovation in diffuse large B-cell lymphoma.
Though in different phases of use and development, antibody-drug conjugates, bispecific antibodies and CRISPR-gene edited chimeric antigen receptor T-cell therapies are all showing potential in the DLBCL space.
“We’re super lucky in this disease to have a bunch of new therapies that were approved this last year or two, or that are going to get approved in the next couple of years,” Joshua Brody, MD, director of the lymphoma immunotherapy program at Tisch Cancer Institute at Mount Sinai, told Healio in an interview.
Antibody-drug conjugates
Recently, many antibody-drug conjugates have received FDA-approval for the treatment of DLBCL.
In the interview, Brody discussed loncastuximab tesirine-lpyl (Zynlonta, ADC Therapeutics), a CD19-targeted antibody-drug conjugate also known as lonca, approved for adults with relapsed or refractory DLBCL.
Patients with relapsed or refractory DLBCL who had received at least two prior lines of therapy who received lonca showed a 48.3% overall response rate — exceeding the threshold established for the study to meet its primary endpoint — and a 24.1% complete response rate, according to results from the phase 2 LOTIS-2 trial published in Lancet Oncology.
Brody also talked about polatuzumab vedotin (Polivy, Genentech), an anti-CD79b antibody drug conjugate also known as pola.
The randomized phase 3 POLARIX study showed that pola added to chemotherapy significantly extended PFS compared with standard first-line treatment for patients with DLBCL. The regimen reduced risk for progression, relapse or death by 27%, according to the results presented at 2021 ASH Annual Meeting and Exposition.
The drug was approved for third-line therapy, but Brody said there was also evidence that it may be helpful even in front-line DLBCL therapy when combined with chemotherapy.
“So that will be a large practice-changing impact — having the option to use these novel immunotherapies in front-line DLBCL therapy,” Brody said.
Bispecific antibodies
Brody called another impressive class of medicines, bispecific antibodies, “the most promising innovative therapy for diffuse large B-cell lymphoma.”
Though no bispecifics are FDA-approved for DLBCL, Brody believes they will become so soon.
“[There are] a couple of different examples, but by far the most common example now is antibodies that bind CD20 on a lymphoma cell and CD3 on a T-cell,” Brody explained in the interview.
One example is mosunetuzumab (Genentech). Results from a pivotal phase 2 dose-expansion study presented at ASH in 2021 showed that mosunetuzumab — a CD20/CD3 bispecific T-cell-engaging antibody — more than quadrupled the complete response rate among patients with relapsed or refractory follicular lymphoma who had received at least two previous lines of therapy.
In DLBCL, what’s “amazing” about bispecifics is the combination of efficacy, safety and ease of use, according to Brody.
“In some patients with diffuse large B-cell lymphoma where other therapies have all failed, some of these still give remissions in 80% of patients and even complete remissions in almost 60% — that is just an order of magnitude better than almost any other medicine,” he said. “Even in patients who have received CAR T cells and the CAR T cells have not been effective, we have had many patients where bispecific antibodies were effective.”
Bispecific antibodies seem to be well-tolerated in DLBCL as well, according to Brody. He said that similar to CAR-T, one main side effect is cytokine release syndrome, but it is often mild, with less than 10% of patients getting high-grade cytokine release syndrome.
Furthermore, bispecifics are easy to use compared with CAR-T, Brody explained.
“We call them off-the-shelf therapies,” he told Healio. “As opposed to autologous CAR T cells — where you have to make it individualized for each patient, it takes 3 weeks to make it and it’s a complex process — these are ready to use the moment the patient walks through the door.”
Brody said bispecific antibodies will probably first be approved for third-line treatment of patients with DLBCL who failed multiple standard therapies; however, he thinks they will “very quickly penetrate up through second-line and even into first-line for many types of lymphoma.”
CRISPR-edited CAR-T
Looking ahead, CRISPR-gene edited cell therapy is in some very early phase clinical trials, though it might take 10 years or more to see results, according to Brody.
“The place in diffuse large B-cell lymphoma where they have the most applicability is allogeneic CAR T cells,” he said. “We already have FDA approved autologous CAR T cells — that are made from the person’s own immune cells, taken out, gene-edited, then reinfused back into the person.”
Brody explained that using autologous CAR T cells is challenging because it takes time to make a new batch for every person; therefore, scientists are trying to invent another type of CAR T-cell therapy that use cells from a third-party donor — called allogeneic CAR T cells — instead of the patient.
“There’s lots of ways to make allogeneic CAR T cells, but one of them can use CRISPR-based gene editing,” Brody said. “The problem with allogeneic CAR T cells is if you inject someone else’s CAR T cells into my body, my body will reject them. So, you have to do a couple of gene edits — manipulations of the genes of that allogeneic CAR T cell — to make it a bit more invisible to the recipient’s immune system.”
However, so far, allogeneic CAR T cells have not shown comparable efficacy to autologous CAR T cells, Brody added.
Addressing unmet need
Even with all these incredible innovations in the works, areas of unmet need remain in the treatment of DLBCL.
Simply put, “we need more effective and safer medicines — also, medicines that are more accessible to patients,” Brody said.
References:
- Budde LE, et al. Abstract 127. Presented at: ASH Annual Meeting and Exposition; Dec. 11-14, 2021; Atlanta.
- Caimi PF, et al. Lancet Onc. 2021;doi:10.1016/S1470-2045(21)00139-X.
- Tilly H, et al. LBA-1. Presented at: ASH Annual Meeting and Exposition; Dec. 11-14, 2021; Atlanta.
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