Multi-Agent Therapy May Overcome CAR T Resistance in B-Cell Malignancies

David B. Miklos, MD, PhD

Treatment with chimeric antigen receptor (CAR) T cells has induced unprecedented overall response rates (ORR) and complete response (CR) rates in patients with relapsed/refractory B cell malignancies. However, up to 50% of patients will relapse.¹

In a presentation at the 25th Annual International Congress on Hematologic Malignancies, David B. Miklos, MD, PhD, associate professor of medicine (blood and marrow transplantation) at the Stanford University Medical Center, suggested that CAR agents targeting multiple antigens might hold the key to breaking through that resistance.

Previous studies have established several factors associated with relapse following CAR T therapy, including loss of the CD19 antigen and aberration in the CD58 antigen, which helps to activate engineered T cells and assists in killing cancer cells.

In a presentation at the 2018 American Society of Hematology Annual Meeting, Jean Oak, PhD, and colleagues found that 8 of 22 (36%) of patients with refractory B cell lymphomas who did not respond to treatment with axicabtagene ciloleucel (Axi-cel) or relapsed after day 28. Five patients (62%) who failed therapy had loss or downregulation of CD19, suggesting that single target antigen loss is a common mechanism of CAR T failure.²

Majzner et al analyzed CD58 status in 51 patients who were treated with axicabtagene ciloleucel for relapsed/refractory B cell lymphomas. Twelve (24%) patients had CD58 mutation or lack of expression, and 11 of those 12 had progressive disease.³

Studies have found CD4+ expression is an indication of patient response. For example, Zinaida Good, PhD, and her colleagues conducted a study seeking to identify cell features distinguishing patients with diffuse large B cell lymphoma (DLBCL) who had durable complete response (CR) at 6 months following axicabtagene ciloleucel treatment from those who had progressive disease. They found that the presence of CD4+ cells on day 7 was highly associated with clinical outcome at 6 months.⁴

At Stanford, investigators have been experimenting with a bispecific bivalent, single polypeptide called a “loop CAR” over the past 4 years to overcome antigen loss. Miklos showed data from a phase 1 dose escalation study of a bispecific anti CD19/CD22 using a self-contained prodigy production system to generate CAR T cells for patients with acute lymphoblastic leukemia (ALL; n = 17), primary mediastinal B-cell lymphoma (PMBCL; n = 2), and DLBCL (n = 20).

“We had day 28 overall response rates in patients with ALL of 100% and we had complete response of 88%,” Miklos said. “The Kaplan-Meier curve shows that the lymphoma fall off after 6 months was somewhere around 50%, but in truth it’s 29%. In truth, we don't think that the lymphoma responses are competitive with the commercially available products.”

Furthermore, 36% of patients with DLBCL or PMBCL and 50% of those with ALL have relapsed. Stanford, and other groups, will reapproach multi-antigen targeting with new constructs and strategies, Miklos said. There is still an unmet need for a commercially available therapy for adults with relapsed/refractory ALL.

Other investigators, however, are have some success. Nirav N. Shah, MD, and colleagues administered bispecific anti-CD20, anti-CD19 (LV20.19) CAR T cells for relapsed/refractory B cell non-Hodgkin lymphoma or chronic lymphocytic leukemia. Eighteen of 22 patients (82%) had an overall response at day 28 with a CR rate of 64%.⁵ This was a phase 1 dose escalation and expansion trial that to evaluate safety, as well as the feasibility of on-site manufacturing using the CliniMACS Prodigy system.

References

1. Cai Q, Zhang M, Li Z. Potential strategies against resistance to CAR T-cell therapy in haematological malignancies. Ther Adv Med Oncol. 2020. doi: 10.1177/1758835920962963
2. Oak J, Spiegel JY, Sahaf B, et al. Target antigen downregulation and other mechanisms of failure after axicabtagene ciloleucel (CAR19) therapy. Blood. 2018;132(Suppl 1): 4656. doi:10.1182/blood-2018-99-120206
3. Majzner RG, Frank MJ, Mount C, et al. CD58 aberrations limit durable responses to CD19 CAR in large B cell lymphoma patients treated with axicabtagene ciloleucel but can be overcome through novel CAR engineering. Presented at: the 62nd ASH Annual Meeting and Exposition; December 5-8, 2020. Abstr 556.
4. Good Z, Spiegel JY, Sahaf B, et al. Identification of two CAR T-Cell populations associated with complete response or progressive disease in adult lymphoma patients treated with Axi-Cel. Blood 2019;134 (Suppl 1):779. doi:10.1182/blood-2019-130815
5. Shah, NN, Johnson, BD, Schneider D, et al. Bispecific anti-CD20, anti-CD19 CAR T cells for relapsed B cell malignancies: a phase 1 dose escalation and expansion trial. Nat Med.2020;1569–1575. doi:10.1038/s41591-020-1081-3