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Genomic features of CAR T treatment failure in patients with lymphoma

Jun 13, 2022
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Learning objective: After reading this article, learners will be able to recall key genomic features that underlie resistance to CD19 CAR T-cell therapy in patients with lymphoma.

CD19-directed chimeric antigen receptor (CAR-19)-reprogrammed autologous T-cells are innovative immunotherapies for heavily pretreated patients with diffuse large B-cell lymphoma (DLBCL); however, across CAR-19 products, ~60% of patients fail to achieve complete tumor eradication and prolonged remission. Inflammatory markers and clinical factors are associated with impaired responses, but tumor-intrinsic resistance drivers are largely undefined.

Here, we summarize the key genomic features underlying anti-CD19 CAR T-cell treatment failure in patients with lymphoma based on the recent article published by Jain, et al., in Blood in 2022.1

Methods

Whole-genome sequencing (WGS) analysis was performed on samples from patients with relapsed or refractory (R/R) DLBCL who had received treatment with CAR-19 T cells (R/R lymphoma cohort, n = 49). To increase the statistical power, WGS data from untreated DLBCL cases from the Pan-Cancer Analysis of Whole Genomes (PCAWG) were also added to the comparative analysis (PCAWG cohort, n = 50).

Results

  • Follow up and clinical outcomes of 47 out of 49 LBCL patients were included in the progression-free survival (PFS) and overall survival (OS) analysis (excluded cases: relapse-only sample with transitory complete remission [n = 1] and early therapy-related death [n = 1] not evaluable for PFS).
  • Demographics, disease characteristics, and responses to CAR-19 for all patients are summarized in Table 1.
  • The median follow-up was 17.3 months.
  • Median OS and PFS for the entire cohort were 11.6 months and 8 months, respectively.
  • The progression-free response was observed in 36.7% of patients.

Table 1. Patient baseline characteristics*

Characteristics, % (unless otherwise stated)

All patients

(N = 49)

Median age (range), years

65 (44–79)

Sex

              Male

77.6

              Female

22.4

Disease

              DLBCL

81.6

              TFL

16.3

              TCLL

2.0

Stage at apheresis

              I/II

16.3

              III/IV

83.7

IPI at apheresis

              1–2

30.6

              3–5

69.4

ECOG Performance Status at apheresis

              0–1

77.6

              2–3

22.4

Prior treatment regimens

              Median (range)

2 (1–6)

Salvage Chemotherapies

              Platinum compounds

81.6

                             Cisplatin

22.4

                             Carboplatin

34.7

                             Oxaliplatin

30.6

              Melphalan

22.4

Previous HDT/ASCR

22.4

Bridging therapy

Yes

69.4

No

30.6

CAR-19 Product

Axicabtagene ciloleucel

91.8

Tisagenlecleucel

4.1

Lisocabtagene maraleucel

4.1

Cytokine release syndrome

              Grade 0

18.4

              Grade 1–2

73.5

              Grade 3–5

8.2

Immune effector cell-associated neurotoxicity syndrome

              Grade 0

32.7

              Grade 1–2

36.7

              Grade 3–4

30.6

CAR-19 Outcome

              Response without progression

36.7

              Response with progression (relapse)

46.9

              Refractory disease

16.3

CAR-19, CD19-directed chimeric antigen receptor; DLBCL, diffuse large B cell lymphoma; ECOG, Eastern Cooperative Oncology Group; HDT/ASCR, high-dose therapy with autologous stem-cell rescue; IPI, International Prognostic Index; TCLL, transformed chronic lymphocytic leukemia; TFL, transformed follicular lymphoma.
*Adapted from Jain, et al.1

Treatment resistance

Overall, markers of genomic complexity (APOBEC and chromothripsis) and specific genomic alterations (RHOA) were associated with resistance to CAR-19 immunotherapy for aggressive B-cell lymphomas. Further details on the genomic complexity and specific genome alterations are summarized below.

Mutational signature gene association

Twelve single base substitution (SBS) mutational signatures were involved in the R/R lymphoma cohort.

  • Presence of APOBEC (SBS2 and SBS13) signatures was associated with significantly worse PFS, with 12/13 (92%) patients progressing (all patients, p = 0.0023; considering only de novo DLBCL [n = 40], p = 0.045).
  • Among additional mutational signatures tested, SBS18 was associated with post-CAR-19 progression in 9/11 (81%) patients (all patients, p = 0.0396; considering only de novo DLBCL [n = 40], p = 0.045).
  • This SBS signature reflects genomic damage from oxygen-radical stress.

Deletion of 3p21.31 (RHOA) association

  • TP53 deletion was the most frequent in 49 R/R patients and mono-allelic or biallelic loss of TP53 was highly prevalent (59.2%; p = 0.76) but did not predict the poor outcome.
  • Focal deletions of 3P21.31 containing RHOA were found to be significantly enriched in the R/R patient’s cohort and independently predicted poor outcomes (p = 0.0013).
  • Loss of RHOA was also associated with poor OS (p = 0.023).

Structural variants

WGS identified four main complex structural variants and complex events:

  • Double minutes (n = 6)
  • Chromothripsis (n = 23)
  • Chromoplexy (n = 18)
  • Templated insertion (n = 11)

Only chromothripsis showed worse PFS (p = 0.026) after CAR-19 treatment, with 18/22 (81.8%) cases (R/R DLBCL) experiencing early progression; however, this was not associated with OS. All de novo DLBCL with double minutes rapidly progressed and died after CAR-19 (p = 0.017 for PFS; p = 0.0011 for OS).

Conclusion

Despite unprecedented overall response rates to CAR-19 in heavily pretreated patients with DLBCL, a significant number of patients often fail to achieve survival outcomes. Genomic complexity and alterations appear to promote an immunosuppressive tumor microenvironment, limiting CAR-19 efficacy. The results discussed here are the foundation of further functional studies that can establish mechanistically how complex lymphoma genomes promote an environment hostile to CAR T cells and possibly other emerging immunotherapies.

  1. Jain MD, Ziccheddu B, Coughlin CA, et al. Whole-genome sequencing reveals complex genomic features underlying anti-CD19 CAR T-cell treatment failures in lymphoma. Blood. Online ahead of print. DOI: 10.1182/blood.2021015008

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