NEW YORK – Autologous CAR T-cell therapy targeting the CD20 antigen may be an effective way to treat advanced non-Hodgkin lymphoma patients for whom anti-CD19 CAR T-cell therapy alone is not sufficient, according to two early clinical trials presented during the American Society of Clinical Oncology's virtual annual meeting.
One study explored a bispecific antibody approach to targeting both CD19 and CD20, and the other investigated targeting CD20 in patients refractory to CD19 CAR T-cell therapy. These different approaches raised questions among oncologists at the meeting as to the best timing and technique for incorporating CD20-targeting therapies into the advanced NHL treatment landscape.
Specifically, in back-to-back presentations, Aibin Liang, an oncologist at the Tongji University in Shanghai, presented data from Phase I clinical trials of two investigational therapies developed by Cellular Biomedicine Group: the bispecific product, C-CAR039, and the CD20-targeting product, C-CAR066. Both studies enrolled patients with relapsed or refractory B-cell NHL, the majority of whom had diffuse large B-cell lymphoma.
Of 27 evaluable patients treated with the bispecific C-CAR039 therapy, the best overall response rate was 92.6 percent, and the complete response rate was 85.2 percent. In an even smaller study involving a heavily pretreated group of 10 patients with B-cell NHL who received the CD20-targeting C-CAR066, the best overall response rate was 100 percent and seven out of 10 patients achieved complete response. All of these patients had received prior anti-CD19 CAR T-cell therapy.
The median number of prior lines of therapy were three and five for the patients treated in the C-CAR039 and C-CAR066 studies, respectively. Though the median duration of response was not yet reached in either study, the six-month progression-free survival estimate for the bispecific C-CAR039 was 83.4 percent, and among the patients treated with the C-CAR066 product, four remained in complete response after 10 months. One patient in each of the two trials experienced cytokine release syndrome of grade three or higher.
"This is impressive and promising, considering these patients were all previously heavily treated with a lack of strong clinical response prior to [this study treatment]," Liang said of the trial involving the CD20-targeting C-CAR066 product. He was similarly encouraged by the C-CAR039 study results.
"CD20 appears to be a viable target in CAR-T technology," Tara Gregory, a hematologist/oncologist at the Colorado Blood Cancer Institute, said in a discussion following Liang's presentations. "The new question is, where do we put it in the non-Hodgkin lymphoma treatment schema?"
Since 2017, three CD19-directed autologous CAR T-cell therapies have entered the commercial market for patients with relapsed or refractory NHL: axicabtagene ciloleucel (Gilead/Kite's Yescarta), tisagenlecleucel (Novartis' Kymriah), and most recently lisocabtagene maraleucel (Bristol Myers Squibb's Breyanzi). For many patients, the treatments have resulted in deep remissions, durable and persistent enough to evoke the word "curative."
That said, the majority of patients who respond to these treatments do still go on to relapse; the 15-month progression-free survival rate for patients treated with axi-cel was 41 percent, the three-year progression-free survival rate for patients treated with tisa-cel was 31 percent, and the one-year progression-free survival rate for liso-cel was 44.1 percent.
For the majority of NHL patients treated with CD-19 CAR T-cell therapy who do go on to experience disease relapse, the next question — and one that has been top of mind for many hematologic oncologists in recent years — is how to preemptively mitigate this relapse from the onset or present another option following relapse. To accomplish this, researchers and drugmakers alike have begun homing in on the reasons why patients may experience relapse following CD19-directed CAR T-cell therapy. These reasons, which Gregory explained in her ASCO discussion, could include loss or modulation of the target antigen with immune escape and lack of CAR T-cell persistence, among other concerns such as dose-limiting toxicities or prohibitive treatment costs.
The developer of these two investigational products, Rockville, Maryland-headquartered Cellular Biomedicine Group, designed them with these relapse mechanisms in mind. With the bispecific therapy, C-CAR039, the idea was to modulate the antigen target such that CD19 would not be downregulated as it often is following CD19-targeted therapy alone. And the idea of CD20-directed CAR T-cell therapy was to overcome CD19 target loss that had occurred already.
"Both abstracts presented today give us insight on how we might deal with the problem of progression post-anti-CD19 CAR T," Gregory said.
Specifically for the CD20-targeting C-CAR066 product, however, Gregory pointed out that when taking a closer look at the antigen expression in four patients who went on to relapse there was a "mixed picture" of antigen modulation versus different mechanisms of relapse. Two of the patients who relapsed had CD19- and CD20-positive disease at the time of relapse, while two patients were negative for both antigens at relapse. All but one of the patients had CAR T-cell persistence at relapse. Longer follow-up in larger patient cohorts will be needed to answer the question as to what, exactly, drove these relapses.
Considering both investigational treatments in the greater landscape of CD19- and CD20-directed lymphoma therapies, Gregory asked whether the sequencing of prior treatment may play a role in relapse. "Does the bispecific construct replace CD19-directed therapies to prevent antigen modulation?" she asked, going on to note that, "currently available and fast upcoming agents … may increase the risk of subclone loss." Beyond the US Food and Drug Administration-approved anti-CD19 CAR T-cell therapies from Kite, Novartis, and BMS, there are also several anti-CD19 monoclonal antibodies on the market or in development, such as tafasitamab (Morphosys' Monjuvi) and CD20/CD3 bispecific T-cell engager therapies currently in clinical trials.
Identifying the ideal sequence of these therapies to minimize relapse potential will take further research. For now, however, the response rates in both Cellular Biomedicine's trials, though involving relatively few patients, were encouraging to Liang and warrant further study. In China, where both of these first-in-human trials took place, Liang shared that Cellular Biomedicine is on track for registrational plans, but that it will take more time to navigate through the regulatory landscape and launch trials of these therapies in the US.
Importantly, both Liang and Gregory pointed out the manufacturing process that Cellular Biomedicine Group used for both therapies. The CliniMACS Prodigy closed system, a highly automated manufacturing method, allowed for a seven- and six-day median manufacturing time in the respective studies of C-CAR039 and C-CAR066, and a leukapheresis-to-infusion time, during which a lymphodepleting regimen is given, of a median of 19 and 20 days, respectively.
This closed-system, tabletop device, a product of Miltenyi Biotec, has also been employed for point-of-care cell therapy development in the US. In a Medical College of Wisconsin study of a similar bispecific CD19/CD20 CAR T-cell therapy approach published in Nature Medicine last fall, researchers embraced the point-of-care aspect of CliniMACS Prodigy, highlighting its advantageous turnaround time. In that study, the system eliminated the need to cryopreserve patients' immune cells and ship them to far-off, industry-operated manufacturing sites, which, in many cases, can add days or weeks to the manufacturing process — time that these heavily pretreated patients may not be able to spare.