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Efficacy and safety of ARI0002h, an academic BCMA-directed CAR T-cell therapy for RRMM

Aug 5, 2022
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Learning objective: After reading this article, learners will be able to cite a new clinical development in relapsed/refractory MM

Despite significant improvements in multiple myeloma (MM) survival in the last year, most patients will relapse and progress, developing relapsed/refractory (RR)MM.1 RRMM that is refractory to the main three groups of treatment agents has a poor prognosis, no clear treatment pathway, and a very poor overall survival. A potential therapeutic option for these patients is immunotherapy using chimeric antigen receptor T-cells (CAR T-cells). In addition, B-cell maturation antigen (BCMA) expression is restricted to plasma cells, making it an optimal target for immunotherapy in MM.

Two CAR T-cell products are currently approved for MM treatment in Europe; idecabtagene vicleucel (our summary of the KarMMa study and the European Commission approval can be read here) and ciltacabtagene autoleucel (our summary of the conditional European Commission approval can be viewed here), which have both demonstrated promising results in heavily treated patients. At the European Hematology Association (EHA) 2022 Congress, Carlos Fernández de Larrea gave a presentation on the CARTBCMA-HCB-01 clinical trial (NCT04309981), which investigated ARI0002h, a CAR T-cell therapy that was developed entirely within an academic institution.1

ARI0002h is a 4-1BB based CAR T-cell product containing a humanized single chain variable BCMA-targeting fragment with proven in vitro and in vivo efficacy.2 In the CARTBCMA-HCB-01 trial, five Spanish centers were included, two of which were involved in ARI0002h production.1

Study design and patient characteristics1

The study design of CARTBCMA-HCB-01 is depicted in Figure 1. Fractionating the infusion of ARI0002h had previously been found to reduce side effects. Initially, there were 44 patients assessed for eligibility and 35 screened. A total of 30 were allocated to the intervention, and five of these patients progressed or died prior to the first infusion with ARI0002h. Following apheresis, 50% of patients required bridging therapy.

Figure 1. Study design*

BCMA, B-cell maturation antigen; BM, bone marrow; CAR T-cell, chimeric antigen receptor T-cell; CRS, cytokine release syndrome; D, day; DLCO, carbon monoxide diffusion capacity; EF, ejection fraction; EGFR, epidermal growth factor receptor; GvHD, graft-versus-host disease; IMiD, immunomodulatory drug; M, month; MRD, minimal residual disease; ORR, overall response rate; OS, overall survival; PB, peripheral blood; PFS, progression-free survival; PI, proteasome inhibitor; PR, partial response; RRMM, relapsed/refractory multiple myeloma; UNL, upper normal limit.

*Adapted from Fernández de Larrea.1
International Myeloma Working Group.

All patients included in the study had been triple exposed to a proteasome inhibitor, an immunomodulatory drug, and to anti-CD38 antibody treatment, and most patients (87%) had received a prior autologous stem cell transplant (Table 1). The median manufacturing time of ARI0002h was 11 days (range, 9–14 days).

Table 1. Patient characteristics*

Characteristic, % (unless otherwise stated)

N = 30

Median age (range), years

61 (36–74)

Sex

 

              Female

40

              Male

60

Heavy chain isotope

 

              IgG

47

              IgA

23

              Bence Jones

23

Plasmacytomas

47

              Extramedullary

20

High-risk cytogenetics

33

Median plasma cells in bone marrow (range), n

11 (0–100)

Median number of previous lines of therapy (range), n

4 (2–10)

              Prior autologous stem cell transplantation

87

              Prior allogeneic stem cell transplantation

13

              Documented triple-exposed

100

              Documented triple-refractory

67

*Adapted from Fernández de Larrea.1
del(17p), t(4;14), and/or t(14;16).
To proteasome inhibitor, immunomodulatory drug, and anti-CD38 antibody treatment.

Results1

Efficacy

The overall response rate (≥ partial response) following the first infusion and at a median follow-up of 17.5 months was 100% (Figure 2), with 63% of patients achieving a stringent complete response.

Figure 2. Response rates in patients treated with ARI0002h*

PR, partial response; sCR, stringent complete response; VGPR, very good partial response.
*Adapted from Fernández de Larrea.1

Minimal residual disease negativity was achieved in 70% of patients 28 days following the first infusion and in 53% of patients after 12 months (Table 2). Median progression-free survival and overall survival were not reached during the median 17.5 month follow-up period.

Table 2. Secondary efficacy outcomes*

Secondary outcome, %

 

MRD negativity in ITT population

 

              Day +28

70

              Day +100

80

              Month 6

67

              Month 12

53

PFS at 18 months

53

OS at 18 months

73

ORR of patients with soft tissue plasmacytoma at Day 100

93

              CR

57

              VGPR

29

              PR

7

              Progressive disease

7

CR, complete response; MRD, minimal residual disease; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; PR, partial response; VGPR, very good partial response.
*Data from Fernández de Larrea.1
Assessed by next-generation flow in bone marrow with a sensitivity of 10−5 to 10−6.
Response was evaluated by PET/CT in 14 patients who had soft tissue plasmacytoma at baseline.

A total of 24 patients went on to have a second “booster” infusion, of which 58% were in stringent complete response at the time of their reinfusion. Of those reinfused, 50% of patients had peripheral blood CAR T-cell expansion, 25% had an improved response, and 17% maintained their response.

Safety and other outcomes

Cytokine release syndrome (CRS) was noted in 90% of patients, which was mostly Grade 1 (67%), and there were no neurotoxic adverse events observed (Table 3). All patients presented with cytopenias beyond 30 days following infusion, and there were three cases of macrophage-activation syndrome, one case of hepatitis-B activation, and one case of colon cancer that was considered unrelated to ARI0002h infusion. There were no CRS or neurotoxic adverse events after the second infusion.

Table 3. Adverse events following infusion with ARI0002h*

Adverse event, % (unless otherwise stated)

 

CRS

90

              Grade 1

67

              Grade 2

23

              ≥Grade 3

0

Median onset of CRS (range), days

8 (1–10)

Median duration of CRS (range), days

4 (1–12)

Use of tocilizumab for CRS

74

Use of corticosteroids

10

Neurotoxicity

0

Hematological toxicity, all (Grade 3/4)

 

              Thrombocytopenia

100 (100)

              Neutropenia

87 (69)

              Anemia

90 (52)

Median duration of hematological toxicity (range), months

 

              Thrombocytopenia

4 (0–14)

              Neutropenia

9 (1–19)

              Anemia

5 (0–20)

CRS, cytokine release syndrome.
*Adapted from Fernández de Larrea.1
Mainly used for persistent Grade 1 CRS.

CAR T-cells were detected in peripheral blood in 62%, 36%, and 20% of patients at Day 100, 6 months, and 12 months, respectively. The median maximum peripheral blood expansion was 14 days (range, 7 days to 6 months) and the median persistence was 5 months (range, 2 months to not reached). Of the patients with available samples, 33% who relapsed still had detectable CAR T-cells in peripheral blood.

Serum BCMA expression was significantly reduced 3 months after infusion (p = 0.0007), with increasing levels associated with relapse. BCMA expression in bone marrow plasma cells at the end of treatment was significantly lower in patients who relapsed compared to baseline expression in all patients (p = 0.0053).

Conclusion

Fernández de Larrea concluded that production of ARI0002h was fast and feasible in patients with RRMM and that infusion resulted in deep and sustained responses with relatively low-grade toxicity in the form of Grade 1 and 2 CRS and no neurotoxic adverse events. Reinfusion was possible in most patients, was not associated with any toxicity, and improved response rates in some patients.

Typically, approved CAR T-cell products have to be ordered from the licensed pharmaceutical company, with manufacturing being subject to capability according to demand.3 This, along with cost, has the potential to result in bottlenecks in the production of CAR T-cell products, which ultimately delay treatment for patients with relapsing disease. As ARI0002h is produced entirely in an academic institution, manufacturing time is low and less likely to be subject to the hold-ups that may be associated with other CAR T-cell products.

Another presentation at the EHA2022 Congress discussed a different academically produced CAR T‑cell product (HSP-CAR30) for patients with Hodgkin lymphoma and CD30+ T-cell lymphoma.4 This phase I study (NCT04653649) of 10 patients demonstrated promising results with an overall response rate of 100% and a CR rate of 50%. The safety profile was favorable, with CRS experienced in 60% of patients (all Grade 1), no neurotoxicity, skin rashes in 40% of patients, and long-lasting cytopenias in only 20% of patients. Both studies1,4 suggest that there is an increasing appetite for academically produced CAR T-cell products that enable rapid access to these therapeutics.

  1. Fernández de Larrea C. Efficacy and safety of ARI0002h, an academic BCMA-directed CAR-T cell therapy with fractionated initial therapy and booster dose in patients with relapsed/refractory multiple myeloma. Oral abstract #S103. European Hematology Association 2022 Congress; Jun 11, 2022; Vienna, AT.
  2. Perez-Amill L, Suñe G, Antoñana-Vildosola, et al. Preclinical development of a humanized chimeric antigen receptor against B cell maturation antigen for multiple myeloma. Haematologica. 2021;106(1):173-184. DOI: 10.3324/haematol.2019.228577
  3. Trias E, Juan M, Urbano-Ispizua A, et al. The hospital exemption pathway for the approval of advanced therapy medicinal products: an underused opportunity? The case of the CAR-T ARI-0001. Bone Marrow Transplant. 2022;57(2):156-159. DOI: 10.1038/s41409-021-01463-y
  4. Caballero A. A phase 1, first-in-human, dose-escalation clinical trial of memory-enriched CD30-CAR T-cell therapy for the treatment of relapsed or refractory Hodgkin lymphoma and CD30+ T-cell lymphoma. Oral abstract #S257. European Hematology Association 2022 Congress; Jun 11, 2022; Vienna, AT.