METHODS FOR THE TREATMENT OF ADULT T-CELL LEUKEMIA/LYMPHOMA

Abstract

Adult T-cell leukemia/lymphoma (ATL) is an aggressive proliferation of mature activated CD4+ T cells associated with the human T-cell lymphotropic virus type I (HTLV-I). The inventors performed an integrated genomic analysis of a retrospective cohort of 62 ATL patients mainly originating from Africa and the Caribbean area. In particular, they identified a subset of mutations in the TCR/NF-KB pathway (PLCG1, CARD11, PRKCB, CBLB, IRF4, CSNK1A1, FYN, RHOA, VAV1). Furthermore, the inventors investigated the effects of an anti-CD3 antibody (OKT3) exposure on 4 ATL samples including 2 cases harboring CARD 11 and PRKCB gain of function alterations and 2 cases without any TCR pathway mutation. The data suggest that ATL harboring TCR pathway mutations clearly responded to anti-CD3 (FIG. 1B, red+OKT3) and died by apoptosis possibly by a mechanism resembling AICD. Importantly, these TCR-pathway/NFKB mutated patients also showed poorer outcome as compared to unmutated cases. Accordingly, the present invention relates to a method of treating adult T-cell leukemia/lymphoma (ATL) in a patient in need thereof comprising administering to the patient a therapeutically effective amount of an anti-CD3 antibody.

Claims

1. A method of treating adult T-cell leukemia/lymphoma (ATL) in a patient in need thereof comprising administering to the patient a therapeutically effective amount of an anti-CD3 antibody.

2. The method of claim 1 wherein the patient harbors at least one gain-of-function mutation in a gene involved in the TCR/NF-κB pathway.

3. The method of claim 1 wherein the patient harbors at least one gain-of-function mutation in PLCG1, CARD11, PRKCB, CBLB, IRF4, CSNK1A1, FYN, RHOA, or VAV1.

4. The method of claim 1 further comprising the steps of i) detecting the at least one gain-of-function mutation in a nucleic acid sample obtained from the patient and ii) administering to the patient the therapeutically effective amount of the anti-CD3 antibody when said at least one gain-of-function mutation is detected.

5. The method of claim 1 wherein the anti-CD3 antibody is a chimeric antibody, a humanized antibody or a human antibody.

6. The method of claim 1 wherein the anti-CD3 antibody is selected from the group consisting of foralumab, muromonab, otelixizumab, teplizumab and visilizumab.

7. The method of claim 1 wherein the anti-CD3 antibody is muromonab having a light chain as set forth in SEQ ID NO:11 and a heavy chain as set forth in SEQ ID NO:12.

8. The method of claim 1 wherein the anti-CD3 antibody is teplizumab having a light chain as set forth in SEQ ID NO:13 and a heavy chain as set forth in SEQ ID NO:14.

9. The method of claim 1 wherein the anti-CD3 antibody is a non-mitogenic anti-CD3 antibody.

10. The method of claim 1 wherein the anti-CD3 antibody is administered to the patient in combination with chemotherapy.

11. The method of claim 3, wherein the at least one gain-of-function mutation in PLCG1 is S345F, Q718K, DelEF730, G869F, S739T, Q916E, E1163K, R48W, D1165H, D1165E or DelDQ1169.

12. The method of claim 3, wherein the at least one gain-of-function mutation in CARD11 is D401N, R179W, R337Q, D401N, R423W, D357V, R377Q, R707C or E626.

13. The method of claim 3, wherein the at least one gain-of-function mutation in PRKCB is D427N, Q433K, A25V or D470H.

14. The method of claim 3, wherein the at least one gain-of-function mutation in CBLB is InsGH296.

15. The method of claim 3, wherein the at least one gain-of-function mutation in IRF4 is K59R, L70V, L64L, E109Q, S11R.

16. The method of claim 3, wherein the at least one gain-of-function mutation in CSNK1A1 is S189R or L160F.

17. The method of claim 3, wherein the at least one gain-of-function mutation in FYN is T15K or R206C).

18. The method of claim 3, wherein the at least one gain-of-function mutation in RHOA is C16Y, C16R, G17V, G124S, D120N, D120V, A161P or A161V.

19. The method of claim 3, wherein the at least one gain-of-function mutation in VAV1 is F69V, L145P, R195C, Q498K, M501L or N505T.

Description

FIGURES

[0040] FIG. 1: (a) TCR-pathway/NFKB mutated patients showed poorer outcome as compared to unmutated cases (b) investigation of the effects of OKT3 exposure on 4 ATL samples including 2 cases harboring CARD11 and PRKCB gain of function alterations and 2 cases without any TCR pathway mutation. These preliminary data suggest that ATL harboring TCR pathway mutations clearly responded to anti-CD3.

EXAMPLE

[0041] We performed an integrated genomic analysis of a retrospective cohort of 62 ATL patients mainly originating from Africa and the Caribbean area. This task was achieved by targeted deep sequencing, SNP array analysis, RNA sequencing and high throughput sequencing (HTS) based mapping of proviral integration sites. The genomic landscape in ATL from these populations overlaps with slight modifications with the genomic alterations observed in ATL from Japan (Kataoka K et al (2015) Nat Genet 47:1304-1315). Interestingly, a subset of mutations (e.g. activating mutations in the NOTCH and JAK/STAT pathways) is shared with T-ALL. Moreover, most of these genetic alterations were not restricted to ATL lymphomagenesis but are common to other non-viral peripheral T-cell lymphomas. Genomic alterations found in ATL were clustered in three main pathways: 46 (74%) patients harbored alterations affecting the TCR/NF-κB pathway (PLCG1, CARD11, PRKCB, CBLB, IRF4, CSNK1A1, FYN, RHOA, VAV1); 26 (42%) harbored alterations (mutations and deletions) affecting T-cell trafficking (CCR4, CCR7, GP183) and 20 (32%) showed alterations in gene involved in immune escape (FAS, HLA-B, B2M, CD58). Importantly, FAS mutations (10/62) predominated in aggressive cases and are identical to germline mutations observed in patients with autoimmune lymphoproliferative syndrome (ALPS), leading to impaired T-cell activation induced cell death (AICD).

[0042] We also developed in collaboration with the GIGA Institute in Liege a protocol of linker-mediated PCR (LM-PCR) followed by high-throughput sequencing (HTS) that is used to map and quantify unique HTLV-1 proviral integration sites. This technique allows us to monitor tumor viral clones during disease course and can be used as a minimal residual disease detection tool (Artesi M et al (2017) Leukemia 31:2532-2535; Rosewick N et al (2017) Nat Comm 8:15264). Under our previously described in vitro conditions (Trinquand A, dos Santos N, Tran Quang C et al (2016) Cancer Discov 6:972-85), we investigated the effects of OKT3 exposure on 4 ATL samples including 2 cases harboring CARD11 and PRKCB gain of function alterations and 2 cases without any TCR pathway mutation. Our data suggest that ATL harboring TCR pathway mutations clearly responded to anti-CD3 (FIG. 1B, red+OKT3) and died by apoptosis possibly by a mechanism resembling AICD. Importantly, these TCR-pathway/NFKB mutated patients also showed poorer outcome as compared to unmutated cases (FIG. 1A).

REFERENCES

[0043] Throughout this application, various references describe the state of the art to which this invention pertains. The disclosures of these references are hereby incorporated by reference into the present disclosure.