Allogeneic CAR T Cell Therapy for Multiple Myeloma Shows Promise

A first-in-class allogeneic CAR T cell therapy regimen demonstrated feasibility and acceptable safety with preliminary evidence of efficacy in patients with heavily pretreated multiple myeloma, according to interim results from the phase 1 UNIVERSAL trial (NCT04093596) published recently in Nature Medicine.

Study participants were treated with ALLO-715, the first anti-B cell maturation antigen (BCMA) allogeneic CAR T cell therapy candidate, after lymphodepletion with fludarabine, cyclophosphamide, and the anti-CD52 antibody ALLO-647.

Allogene Therapeutics (Allogene) developed ALLO-715 and ALLO-647 and funded the single-arm, open-label, dose-escalation trial, which is ongoing and continues to enroll patients at Memorial Sloan Kettering Cancer Center (MSK) and 12 other sites across the United States. ⁽¹⁾

Highlights of the interim results: ⁽¹⁾

• 43 patients were successfully treated, with nearly 90% receiving allogeneic CAR T cells five days after enrolling — more than six weeks earlier than possible with autologous CAR T cell therapy options.
• The safety profile for ALLO-715 was encouraging and in line with anti-BCMA autologous-targeted cell therapies. No graft-versus-host disease (GVHD) was reported.
• Among 24 patients who received the optimal dose of ALLO-715, the objective response rate (ORR) was 71%, including 11 patients (46%) with very good partial response or better and 6 patients (25%) who experienced a complete response. The median duration of response (mDOR) was 8.3 months.

“Initiating therapy right away is essential, especially in heavily pretreated patients with relapsed/refractory disease who don’t have time to wait for autologous CAR T cell therapy,” said multiple myeloma specialist Sham Mailankody, MBBS, Associate Attending Physician at MSK, and lead author of the paper. “These interim phase 1 results are a strong proof of concept that allogeneic CAR T cells could be used for multiple myeloma.”

Multiple Myeloma and Current Treatment Options

Despite recent treatment advances, multiple myeloma continues to be an incurable blood cancer. Standard immunomodulatory drugs, proteasome inhibitors, and anti-CD38 monoclonal antibodies prolong survival. However, patients ultimately relapse, with each line of therapy making the cancer more refractory to treatment. ⁽²⁾

BCMA is expressed mainly on mature B lymphocyte and plasma cells ⁽³⁾ and plays a key role in the survival and proliferation of multiple myeloma cells. ^(4) (5) Newer therapies targeting BCMA, including bispecific antibodies ^(6) (7) and autologous CAR T cell therapies, ^(8) (9), have demonstrated activity.

In particular, two autologous BCMA-targeted CAR T cell therapies have demonstrated high response rates and durability. Idecabtagene vicleucel (ide-cel) achieved an ORR of 72% and mDOR of 11 months, ^(8) (10) and ciltacabtagene autoleucel (cilta-cel) achieved an ORR of 98% with an mDOR not yet reached. ^(9) (11)

“While autologous CAR T cell therapies represent a significant advance for patients with multiple myeloma, several challenges prevent widespread access, including manufacturing constraints, out-of-specification product, and lengthy vein-to-vein time requiring bridging therapy for most patients,” says Dr. Mailankody. “An off-the-shelf, allogeneic CAR T product can be accessed quickly on demand and at scale with no need for bridging therapy.”

The First Allogeneic CAR T Cell Therapy Regimen

ALLO-715 is the first allogeneic, anti-BCMA CAR T cell therapy engineered to minimize the risk of GVHD and CAR T rejection. Allogene manufactured ALLO-715 for the study from peripheral blood mononuclear cells collected via leukapheresis from three healthy volunteer donors. The product is provided in frozen suspension for infusion. ⁽¹⁾

ALLO-715 contains a self-inactivating, third-generation, recombinant lentiviral vector that expresses a second-generation, anti-BCMA CAR containing a single-chain variable fragment derived from a human anti-BCMA antibody. ALLO-715 is engineered with two knockouts: the T cell receptor alpha constant (TRAC) knockout reduces the risk of GVHD, and the knockout of CD52, a cell-surface protein found on various immune cell types, reduces the risk of host-versus-graft rejection of the transplanted cells. ⁽¹⁾

ALLO-647, part of the lymphodepletion regimen, depletes CD52-positive immune cells, thereby lowering the risk of host-versus-graft rejection and allowing the ALLO-715 CAR T cells to expand and persist. ⁽¹⁾

Study Design

The dose-escalation study evaluated four target doses of ALLO-715. Increasing dose levels were tested sequentially, and all patients received all doses according to their assigned escalation. Investigators also assessed several lymphodepletion regimens with different doses of ALLO-647. ⁽¹⁾

Eligible patients were 18 years or older with relapsed/refractory multiple myeloma after receiving at least three previous lines of therapy and showing measurable disease progression within 60 days of their last dose. Patients treated previously with a BCMA-targeted CAR T therapy were excluded. ⁽¹⁾

Among 48 patients recruited between September 2019 and October 2021, five did not receive lymphodepletion due to disease progression, death, or acute events. A total of 43 patients completed lymphodepletion and received ALLO-715. The median time from enrollment to the start of lymphodepletion was 5 days (range of 0 to 20 days). No patients received bridging therapy. ⁽¹⁾

Preliminary Results

The primary objectives of the present analysis were the safety and tolerability of ALLO-715 at increasing dose levels and a safety assessment of ALLO-647 as part of the lymphodepletion regimen in combination with fludarabine and/or cyclophosphamide.⁽¹⁾

The safety profile for ALLO-715 was in line with anti-BCMA autologous-targeted CAR T therapies. Grade 3 or higher adverse events were observed in 38 patients (88%). Cytokine release syndrome (CRS) and neurotoxicity were observed in 24 patients (56%) and 6 patients (14%), respectively, with only one grade 3 case of CRS and no grade 3 or higher cases of neurotoxicity — somewhat lower than observed with autologous anti-BCMA CAR T cell therapies. ^{(10) (11) (12)} Prolonged cytopenia rates were 19%, in line with autologous CAR T cell therapies. ⁽¹⁾

Notably, there were no cases of GVHD, suggesting that the TRAC knockout is effective for mitigating GVHD risk. ⁽¹⁾

Lymphodepletion with ALLO-647 provided a prolonged effect with no increase in grade 3 or higher infections compared with anti-BCMA autologous-targeted cell therapies. ^{(8) (10) (13) (14)} Infections occurred in 23 patients (54%), including grade 3 or higher infections in 10 patients (22%). Cytomegalovirus viral reactivations were observed in 33% of patients, revealing the importance of monitoring and considering anti-infective prophylaxis for cytomegalovirus in this patient population. ⁽¹⁾

The secondary objectives of the present analysis included assessing ORR and mDOR. In a group of 24 patients who received lymphodepletion with ALLO-647 and the optimal ALLO-715 dose of 320 x 10 ⁽⁶⁾cells, the ORR was 71% with an mDOR of 8.3 months. Within this group, among 10 patients who received a 60 mg dose of ALLO-647, the ORR was 80% with an mDOR not yet reached. ⁽¹⁾

Advancing CAR T Cell Therapy Research for Mulitple Myeloma

The UNIVERSAL phase 1 study also includes an evaluation of ALLO-715 in combination with nigrogacestat, an investigational gamma secretase inhibitor that cleaves BCMA, and an assessment of a consolidation approach that provides two doses of ALLO-715, about two weeks apart. These study elements are not part of the present paper and will be reported in the future.

Learn more about the phase 1 UNIVERSAL study at MSK for patients with relapsed/refractory multiple myeloma.

Dr. Mailankody says Allogene and other manufacturers are developing more allogeneic CAR T cell therapy candidates. “We don’t know yet if we will end up using this exact product version in the future,” he says. “But an allogeneic approach to CAR T therapy is a significant advance for patients with heavily pretreated multiple myeloma. Additionally, the concept of knocking out CD52 and TRAC to pave the way for allogeneic CAR T cells is an exciting approach that may benefit other blood cancers and some solid tumors in the future.”

MSK multiple myeloma specialists are dedicated to advancing new treatment options for patients. Dr. Mailankody was also lead author on a phase 1 study (NCT04555551) of a novel autologous CAR T cell therapy targeted to G protein-coupled receptor, class C, group 5, member D (GPRC5D), an approach that built on MSK lab research. The study results, published recently in The New England Journal of Medicine, confirmed that GPRC5D is an active immunotherapeutic target in patients with multiple myeloma. ⁽¹⁵⁾ A new trial at MSK that builds on this learning is now underway.

The allogeneic CAR T cell therapy research was sponsored and funded by Allogene Therapeutics. Dr. Mailankody has received consulting fees from Evicore, Optum, BioAscend, Janssen Oncology, and Legend Biotech. He has received honoraria from OncLive, Physician Education Resource, MJH Life Sciences, and Plexus Communications. MSK receives research funding from the National Cancer Institute, Janssen Oncology, Bristol Myers Squibb, Allogene Therapeutics, Fate Therapeutics, and Takeda Oncology for conducting research.