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Anti-CD22 CAR T-cell potency and toxicity is affected by CD4/CD8 T-cell selection

Aug 27, 2020
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Despite recent advances made with CD19-targeted immunotherapies, there are limited effective treatment options for patients with B-cell acute lymphoblastic leukemia (ALL) who relapse after these treatments, and novel treatment options are warranted. One such strategy could be to target CD22 (an alternative B-cell antigen).

Nirali Shah and colleagues performed a single-center, phase I, 3+3 dose-escalation and expansion trial to assess the outcome of the largest patient cohort (children and young adults with relapsed/refractory CD22+ hematologic malignancies) treated with CD22 chimeric antigen receptor (CAR) T cells, which was recently published in the Journal of Clinical Oncology.1

Study design

The inclusion criteria for this study were patients aged 3–30 years, with CD22+ malignancy and good organ function.  If patients received prior CAR T cells, they needed to have < 5% circulating CAR T cells. Patients were excluded from initial enrollment if they had isolated central nervous system (CNS) or CNS3 diseases. Yet, patient with active CNS disease could be included in a separate cohort.

Dose levels (DLs) were calculated (based on transduced CAR T cells per kg) as follows: DL1, 3 × 105/kg; DL2, 1 × 106/kg; DL3, 3 × 106/kg. In this study, all participants received fludarabine 25 mg/m2/day on Days -4, -3, and -2, and cyclophosphamide 900 mg/m2 on Day -2, with CD22 CAR T-cell infusion on Day 0.

The primary objectives were to evaluate safety and assess toxicity amid dose finding and manufacturing feasibility, while secondary objectives were evaluation of efficacy, CAR T-cell persistence, reinfusion strategies, and cytokine profiling.

Hemophagocytic lymphohistiocytosis (HLH) was retrospectively defined if peak ferritin level was > 100,000 μg/L, and at least two of the following criteria were met: hepatic aminotransferases or bilirubin Grade ≥ 3, creatinine Grade ≥ 3, pulmonary edema Grade ≥ 3, and/or evidence of hemophagocytosis on bone marrow evaluation.

Two patients, who experienced relapse following first infusion of the product, had a new apheresis product collected and re-enrolled as new unique participants.

Due to two lethal events at DL2 (gram-negative sepsis with multiorgan dysfunction and fulminant capillary leak syndrome with acute respiratory distress syndrome) the protocol was revised to incorporate use of corticosteroids and/or tocilizumab in patients with proof of pulmonary toxicity.

After an initial expansion at DL2 (1 × 106/kg) it was decided to integrate CD4/CD8 T-cell selection (TCS) of all starting apheresis material in order to improve CAR T-cell manufacturing feasibility and to lower product variability between patients. This TCS led to enhanced transduction efficiency, better expansion, and improved consistency and recovery.

However, due to this modification, more patients suffered from heightened inflammatory reactions, and the final dose was de-escalated for all subsequent participants to DL1-TCS (3 × 105/kg; n = 25).

Results

Out of 64 participants enrolled in the study, 58 patients received infusion and were assessed for toxicity as shown in Table 1.

Table 1. Participant characteristics1

CAR, chimeric antigen receptor; DL, dose level; HSCT, hematopoietic stem-cell transplantation; M2, marrow has 5–25% leukemic blasts; TCS, T-cell selection.

DL represents dose of transduced CAR T cells/kilogram.

Characteristic

All Participants

(treated)

DL1

(3 × 105/kg)

DL2

(1 × 106/kg)

DL3

(3 × 106/kg)

DL2-TCS

(1 × 106/kg)

DL1-TCS

(3 × 105/kg)

No. of participants

58

6

18

2

7

25

Median age, years (range)

17.5
(4.4-30.6)

21.3
(7.3-22.7)

16.7
(8.0-30.6)

17.1
(7.9-26.4)

12.8
(4.4-28.9)

15.8
(4.7-30.4)

Prior HSCT, n

39

6

13

2

6

12

Prior CD19-targeted therapy, n

51

6

13

 2

7

23

Prior CD19 CAR therapy, n

36

6

11

1

5

13

Prior blinatumomab, n

23

1

4

2

2

14

Prior inotuzumab, n

14

1

4

1

3

5

Prior CD22 CAR exposure, n

5

0

0

0

2

 3

Any CD19-negative

Population, n

33

4

9

0

5

15

≥ M2 marrow, n

44

4

11

2

6

21

Isolated CNS disease, n

1

0

1

0

0

0

 

  • Out of 58 patients who received infusion, 50 (86.2%) patients developed cytokine release syndrome (CRS). Day 7 post infusion represents the average time to CRS onset.
  • 19 (32.8%) patients out of 58 patients exhibited one or more neurological issues. With the exception of one patient who had Grade 4 intracranial hemorrhage (ICH) and was treated at DL1-TCS, all other patients had Grade 1 and 2 neurological toxicities.
  • Out of 58 patients, 14 (24.1%) developed disseminated intravascular coagulation, 9 (15.5%) symptomatic coagulopathy, 19 (32.7%) HLH, 3 (5.2%) capillary leak syndrome, and 3 (5.2%) atypical hemolytic uremic syndrome.
  • HLH occurred with a median onset of 14 days (range, 7–26) post-CAR T-cell infusion and was always preceded by CRS. It was seen in a total of 19 (38%) patients, most strongly at DL2-TCS in 5 of 7 patients, leading to a dose reduction to DL1-TCS where 11 of 25 patients developed HLH. The extent of HLH seen in the TCS cohorts was linked to the manufacturing change.
  • In five patients, HLH/macrophage-activation syndrome (MAS) manifestations were self-resolved. But, due to worsening laboratory parameters or clinical symptoms in 14 patients, HLH/MAS-directed treatment was initiated with systematic use of anti-interleukin (IL)-1 receptor antagonist (anakinra). Out of those 14 patients, treatment was started with anakinra alone in three patients, corticosteroids plus anakinra in five patients, or corticosteroids alone in six patients. All treated patients showed resolution of HLH/MAS-like manifestations, with no apparent negative effect on response or CAR T-cell expansion.
  • Cytokine profiling showed that IL-10, IL-8, IL-6, interferon gamma, IL-15, tumor necrosis factor-a, and IL-1B were present at greater amount in those with CD4/8-TCS than in those with CD3/ CD28 enrichment, supporting anakinra use in these patients.

Toxicity management and response profiles of 58 patients are shown in Table 2 and Table 3.

Table 2. Toxicity, CRS Management1

Variable

All

Participants

DL1

(3 × 105/kg)

DL2

(1 × 106/kg)

DL3

(3 × 106/kg)

DL2-TCS

(1 × 106/kg)

DL1-TCS

(3 × 105/kg)

No. of participants

58

6

18

2

7

25

Participants with CRS, n

50 

3

16

2

6

23

CRS grades ≥ 3 (ASTCT CRS scale), n

12

1

3

0

1

7

Any neurotoxicity, n

19

2

4

3

9

Severe neurotoxicity, n

1

0

0

0

1

Received tocilizumab, n

23

0

3

0

4

16

Received corticosteroids, n

18

0

2

1

4

13

Developed DIC, n

14

0

6

0

4

4

Developed symptomatic coagulopathy, n

9

0

3

0

4

2

Developed HLH, n

19

0

3

0

5

11

Developed CLS, n

3

0

1

0

0

2

Developed aHUS, n

3

0

0

0

1

2

Grade 5 events, n

2

0

2

0

0

0

aHUS, atypical hemolytic uremic syndrome; ASTCT, American Society for Transplantation and Cellular Therapy; CLS, capillary leak syndrome; CRS, cytokine release syndrome; DIC disseminated intravascular coagulation; DL, dose level; HLH, hemophagocytic lymphohistiocytosis; TCS, T-cell selection.

CRS as graded per Lee et al., (2014).2

 

Table 3. Response Profile1

CR, complete response; DL, dose level; MRD, minimal residual disease; TCS, T-cell selection.

Response

All

Participants

DL1

(3 × 105/kg)

DL2

(1 × 106/kg)

DL3

(3 × 106/kg)

DL2-TCS

(1 × 106/kg)

DL1-TCS

(3 × 105/kg)

CR, n

40  

1

13

1

6

19

MRD-negative CR rate among those with CR, n

35 

10 

0

6

18

 

  • Of the 40 (70.2%) patients who achieved a complete remission, 35 (87.5%) were minimal residual disease (MRD)-negative by flow cytometry, and responses were unaffected by prior CD19 CAR-T cell therapy or HSCT.
  • However, in patients with previous CD22-targeted therapy, MRD-negative complete remission rates were lower, with higher rates of residual CD22-dim disease and shorter durations of remission (3 months vs 6 months) when compared with those who had not received CD22-targeted therapy. Of the 30 patients who relapsed, the majority had CD22-negative/dim disease.
  • The median overall survival and relapse-free survival in participants who achieved a complete remission were 13.4 months and 6.0 months, respectively
  • Receiving hematopoietic stem-cell transplantation was favorably associated with relapse-free survival and event-free survival, but not with overall survival
  • After a median follow-up of 9.7 months, 21 patients were alive, and 11 were in remission. One patient was in an ongoing complete response ≥ 3.5 years after infusion, with no interval therapy.

Conclusion

In conclusion, the data from this trial confirm that CD22 CAR T-cell therapy is feasible in patients with relapsed ALL and leads to high remission rates, which have allowed these patients to move to allogeneic transplantation. CD22 CAR T could therefore be considered as an effective alternative treatment option at relapse after CD19 CAR T-cell therapy, supporting further development in a phase II trial. However, CD22 CAR T-cell therapy appears to come with a novel toxicity profile, further enhanced after changes in the manufacturing process. Management of the new side effect profile, notably HLH and capillary leak syndrome, warrants further clinical evaluation.

  1. Shah NN, Highfill SL, Shalabi H, et al. CD4/CD8 T-cell selection affects chimeric antigen receptor (CAR) T-cell potency and toxicity: updated results from a phase I anti-CD22 CAR T-cell trial. J Clin Oncol. 2020:38(17);1938-1950. DOI: 10.1200/JCO.19.03279

  2. Lee DW, Gardner R, Porter DL, et al. Current concepts in the diagnosis and management of cytokine release syndrome. Blood. 2014:124(2);188-195. DOI: 10.1182/blood-2014-05-552729

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