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L. Rasche et al.
Table 3. Clinical trials with B-cell maturation antigen chimeric antigen receptor T cells.
CAR Construct
Cell dose
9x106 cells / kg bw
C1: 1-5x108 total cells
C2: Cy+1-5x107 total cells C3: Cy+1-5x108 total cells
50-800x106 total cells 150-450x106 total cells
med. 0.5x106 cells / kg bw med. 0.71x106 cells / kg bw
Trial
First-in-humans Phase I
CRB-401 (Phase I)
KarMMa
LEGEND-2 (Phase I)
CARTITUDE-1 (Phase I / II)
Sponsor
NIH UPenn
BMS / Celgene
BMS / Celgene
China Janssen
N ORR CR
16 81% 13%
25 48% 8%
C3:64% 4.2 mo
PFS
7.8 mo
Cytopenia 3/4 CRS ICANS Ref.
BCMA CD28
BCMA 4-1BB
BCMA CD28
BCMA CD28
BCMA 4-1BB
BCMA 4-1BB
/ /
/ /
/ /
MDOR
38% 6% 32% 12%
7% 2% 5% 3%
7% 0% 5% 2%
44,45 37
46,47 45, 48,49
50-52 52-55
grade 3/4
prolonged 13%
neutropenia 44% thrombopenia 28%
leukopenia 61% neutropenia 89% thrombopenia 57%
leukopenia 39% neutropenia 89% thrombopenia 52%
leukopenia 30% thrombopenia 23%
leukopenia 61% neutropenia 95% thrombopenia 69%
grade 3/4 grade 3/4
Ide-cel (bb2121)
Ide-cel (bb2121)
Cilta-cel (LCAR-B38M)
Cilta-cel (JNJ-4528)
60 62% 39% 128 73% 33%
57 88% 74% 97 97% 67%
8.8 mo 8.8 mo
19.9 mo
NR
FU 12.4 mo
CAR: chimeric antigen receptor; ORR: overall response rate; CR: complete response; PFS: progression-free survival; CRS: cytokine release syndrome; ICANS: immune effector cell-associated neuro- toxicity syndrome; NIH: National Institutes of Health; UPenn: University of Pennsylvania; BMS: Bristo-Myers Squibb; Ide-cel: idecabtagene vicleucel; Cilta-cel: ciltacabtagene autoleucel; NR: not report- ed; FU: follow-up.
plasma cells makes this antigen an ideal target protein for T-cell-based immunotherapy. However, a number of other cell surface receptors share these characteristics and are being targeted with TCE in ongoing trials. This is of particular interest, as BCMA downregulation37 and even irreversible loss38 of BCMA expression has been reported following treatment with targeted immunotherapies.
Talquetamab
Talquetamab is a GPRC5D x CD3 TCE which has been evaluated in a dose-escalation phase I study,39 in which it was administered both intravenously and subcutaneous- ly. A total of 175 patients were treated and a dose of 405 μg/kg was defined as the recommended phase II dose. At this dose, 69% (9/13) of patients responded, including two who had stringent complete responses. Dose-limit- ing toxicities included increased lipase (grade 4) and mac- ulopapular rash (grade 3) in one and two subjects, respec- tively. Skin-related off-target effects and nail disorders were seen in a significant proportion of patients. CRS occurred in 55% of the patients but was generally low grade with no grade ≥3 CRS in those administered the product subcutaneously.
Cevostamab
This FcRH5 x CD3 humanized IgG-based TCE is being evaluated in an ongoing phase I, dose escalation and expansion trial (NCT03275103). FcRH5 is expressed on MM cells and plasma cells and, to a lesser extent, on nor- mal B cells.7 The ORR was 53% (18/34) in patients receiv- ing active doses, and six patients achieved minimal resid- ual disease negativity at a threshold of 105. CRS occurred in 76% of patients with one patient experiencing grade 3 CRS.40 The dose escalation and expansion phase is ongo- ing.
In summary, there is an extensive pipeline of TCE tar- geting BCMA and other antigens, with response rates to these products being between 50% and 80%, including some deep responses in heavily pretreated patients. CRS is common during the first cycle of treatment, but is man- ageable with step-up dosing schedules and the use of pro-
phylaxis. Short intravenous infusions or subcutaneous formulations offer convenient administration in the out- patient setting. Several other TCE are in early clinical development with clinical data yet to be reported.
Chimeric antigen receptor T-cell approaches
CAR T cells have emerged as a highly promising new therapeutic approach in cancer. The first success was observed with CAR T cells targeting CD19 in B-cell malignancies such as aggressive lymphoma and acute lymphoblastic leukemia. The main toxicities are CRS, immune effector cell-associated neurotoxicity syndrome (ICANS) and cytopenia, which may be prolonged.41,42
There has recently been progress in developing CAR T cells to treat MM.43 T cells are harvested by an unstimu- lated leukapheresis and genetically modified to generate CAR T cells using a lentiviral or retroviral fusion-con- struct with an antibody fragment to recognize the tumor antigen and the T cell receptor signaling domain CD3ζ to activate the modified T-cell (first generation). To further enhance T-cell activation one (second generation) or two (third generation) co-stimulatory domains, usually derived from CD28 or 4-1BB, are added. After in vitro expansion the CAR T cells are re-transfused after lym- phodepleting chemotherapy with cyclophosphamide and fludarabine to enhance expansion of the modified T cells.
Several potential targets have been identified on myelo- ma cells with data for BCMA being the most mature (Table 3). The first-in-human trial was conducted at the National Institutes of Health employing a BCMA-CD28 CAR. Sixteen heavily pretreated patients who received the highest CAR T-cell dose (9x106 cells/kg) had an ORR of 81% including 13% with complete responses and a median PFS of 7.8 months. CRS grade 3/4 was seen in 38%, ICANS grade 3/4 in 6% and prolonged cytopenia grade 3/4 in 13% of the patients.44,45
Another phase I trial from the University of Pennsylvania using a BCMA-4-1BB CAR included 25 patients with RRMM. The ORR was 48% with 8% hav- ing a complete response and a median duration of
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