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B. Bruno et al.
MM.62 One study evaluated CD19 CAR-T following sal- vage high-dose therapy and autologous transplantation. All ten patients had shown a PFS shorter than 1 year from a previous transplant. Two experienced a longer PFS after transplant plus CD19 CAR-T therapy, compared with first autologous stem-cell transplantation. Only one patient experienced CRS (grade 1).63
Chimeric antigen receptor T-cell toxicity in multiple myeloma
CAR-T may induce several life-threatening side effects such as CRS and ICANS.64 Hemophagocytosis and pro- longed cytopenias may also occur. CRS mainly consists of fever, hypotension, hypoxia and organ toxicity, which may result in organ failure. ICANS may include several symptoms: impaired concentration, cognitive disorders, confusion, agitation, tremor, lethargy, aphasia, delirium, somnolence, seizures, motor weakness, paresis or signs of intracerebral pressure. ICANS usually occurs during or after CRS and may manifest a biphasic course, in about 10% of cases up to 4 weeks after CAR-T infusion. A ten- point neurologic assessment, at least twice a day, using the ICE screening tool is recommended for early detection.64 Reported toxicity rates of hallmark studies are illustrated in Table 3. Importantly, a broad consensus statement offering updated comprehensive recommendations for the treatment of toxicities associated with immunotherapies has been recently published.65 Though many aspects remain unknown, mechanisms underlying CRS and ICANS have become clearer. Several factors contribute to different toxicity rates.65 Moreover, incidence and severity of adverse effects vary between diseases. While the inci- dence of any grade CRS is comparable between diseases, CRS severity (≥grade 3) is highest in patients with ALL and lowest in MM. This may partly be explained by dis- ease burden and aggressiveness. In addition, earlier treat- ment of CAR-T side effects with more experience in
Table 3. Toxicity of CAR-T cell treatment in multiple myeloma
recent trials may have contributed to reduce progression to higher grades of toxicity. Unlike CRS, incidence of ICANS is higher in ALL or lymphoma and appears lower in MM patients. Other factors such as tumor burden, prior treatment, CAR-T constructs and dose administered have been described. Several grading systems have been pro- posed to assess CRS and ICANS. Recently, the American Society for Transplantation and Cellular Therapy grading system was compared to other grading scores in two adult populations.66 Interestingly, incidence of CRS and ICANS were similar in all grading systems. By contrast, only 25% and 54% of patients were however assigned to the same severity grade given the discrepancies in scoring adverse symptoms. These differences may also easily lead to inconsistent management guidelines among studies. Overall, efforts should be made to unify grading systems be used across clinical trials.
Improving chimeric antigen receptor T-cell ther- apies in multiple myeloma
Despite numerous autologous CAR-T products under development67,68 and encouraging high response rates,69 none have yet been approved, with BCMA remaining the best evaluated target.49,51,69 Other limitations are toxicities, resistance mechanisms, availability, and patient manage- ment (Table 4). Here we highlight possible strategies for improvement.70,71
Safety
Preventing cytokine release
The pro-inflammatory interleukin-6 (IL-6) is increasing- ly acknowledged to play a central role in the pathogenesis of CRS.47 A recent study designed a nonsignaling mem- brane-bound IL-6 receptor (mbaIL6) which was constitut- ed by a scFv derived from an antibody against IL-6, and linked to a transmembrane anchoring peptide. The study identified expression of mbaIL6 on the surface of T cells
CAR-T
BCMA/CD28
BCMA/4-1BB
BCMA/4-1BB
BCMA/4-1BB
BCMA/CD28
Construct
LCAR-B38M (JNJ-4528)
JNJ-4528
bb2121
Cell dose
9x106 cells / kg bw
C1: 1-5x108 total cells
C2: Cy+1-5x107 total cells C3: Cy+1-5x108 total cells
med. 0.5x106 cells / kg bw
med. 0.73x106 cells / kg bw
50-800 x 106 total cells
Trial
First-in-humans
Phase I
LEGEND-2
CARTITUDE-1 (Phase I/II)
CRB-401 (Phase I)
Sponsor N
NIH 16
UPenn 25
China 57 (Phase 1)
Janssen 29
BMS / Celgene 33
Cytopenia 3/4
leucopenia 94% neutropenia 88% thrombopenia 63% prolonged 13%
leucopenia 44% neutropenia 44% thrombopenia 28% prolonged n.r.
leucopenia 30% neutropenia n.r. thrombopenia 23% prolonged 16%
leucopenia 59% neutropenia 100% thrombopenia 69% prolonged n.r.
leucopenia 58% neutropenia 85% thrombopenia 45% prolonged n 3% t 35%
CRS 3/4
38%
32%
7%
7%
6%
ICANS 3/4 Ref
6% 30
12% 49
0% 53
3% 48 68
3% 51
CRS: cytokine-release syndrome; ICANS: immune effector cell-associated neurotoxicity syndrome; Ref.: references; bw: body weight; C: cohort; Cy: cyclophosphamide; n.r.: not reported; n: number of patients.
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haematologica | 2021; 106(8)