CD19/C22 CAR T-CELL TREATMENT OF HIGH RISK OR RELAPSED PEDIATRIC ACUTE LYMPHOBLASTIC LEUKEMIA

1 . A method of treating high risk/relapsed CD19+ or CD22+ haematological malignancy in a patient comprising administering autologous CD19/22 CAR T-cells to the patient.

2 . Autologous CD19/22 CAR T-cells for use in the treatment of high risk/relapsed CD19+ or CD22+ haematological malignancy.

3 . (canceled)

4 . The method of claim 1 , wherein the age of the patient is twenty-four years or younger.

5 . The method of claim 1 , wherein the haematological malignancy is acute lymphoblastic leukemia (ALL), or a CD19+ or CD22+ lymphoma.

6 . The method of claim 5 , wherein the lymphoma is Burkitt's lymphoma.

7 . The method of claim 1 , wherein the patient has:

a) resistant disease (>5% blasts) at end of UKALL 2019 guidelines or equivalent induction,

b) ALL with persisting high level MRD at 2nd time point of frontline national protocol (currently MRD>10 −4 at week 14 UKALL2019 guidelines or equivalent),

c) high risk infant ALL (age <6 months at diagnosis with MLL gene rearrangement and either presenting white cell count >300×10 9 /L or poor steroid early response (circulating blast count >1×10 9 /L following 7 day steroid pre-phase of induction as per national guidelines or equivalent),

d) intermediate risk infant ALL with MRD>10 −3 at end of induction following national guidelines or equivalent),

e) high risk first relapse (as defined by updated IntreALL 2019 classification: bone marrow or combined relapse within thirty months of diagnosis),

f) standard risk relapse in patients with high risk cytogenetics (defined as BCR-ABL, KMT2A rearrangement, near-haploidy (<30 chromosomes) and low hypodiploidy (30-39 chromosomes), iAMP21 and TCF3-HLF translocations),

g) standard risk relapse with bone marrow minimal residual disease (MRD) >10 −3 at end of re-induction,

h) any refractory relapse of ALL (defined as >1% blasts by flow cytometry after at least one cycle of standard chemotherapy), or

i) any relapse of CD22+ lymphoma.

8 . The method of claim 7 , wherein the patient has an isolated CNS relapse meeting one or more of a)-i).

9 . The method of claim 1 , wherein the patient has received one or more lines of prior therapy.

10 . The method of claim 9 , wherein the patient has received one or more of inotuzumab ozogamicin, blinatumomab and tisagenlecleucel.

11 . The method of claim 1 , wherein the patient is administered a single dose of 0.5×10 6 CAR T-cells/kg, 0.75×10 6 CAR T-cells/kg, 1×10 6 CAR T-cells/kg, or 1.2×10 6 CAR T-cells/kg.

12 . The method of claim 11 , wherein the administration is an intravenous injection, preferably through a Hickman line or peripherally inserted central catheter.

13 . The method of claim 1 , wherein the CD19/22 CAR T-cell product expresses a chimeric antigen receptor (CAR) comprising a CD19-binding domain which comprises;

a) a heavy chain variable region (VH) having

complementarity determining regions (CDRs) with

the following sequences:

(SEQ ID NO: 1)

CDR1 - GYAFSSS;

(SEQ ID NO: 2)

CDR2 - YPGDED

(SEQ ID NO: 3)

CDR3 - SLLYGDYLDY;

and

b) a light chain variable region (VL) having CDRs

with the following sequences:

(SEQ ID NO: 4)

CDR1 - SASSSVSYMH;

(SEQ ID NO: 5)

CDR2 - DTSKLAS

(SEQ ID NO: 6)

CDR3 - QQWNINPLT.

14 . The method of claim 13 , wherein the CD19-binding domain comprises a VH domain having the sequence shown as SEQ ID NO: 7 and/or or a VL domain having the sequence shown as SEQ ID NO: 8 or a variant thereof having at least 95% sequence identity.

15 . The method of claim 14 , wherein the CD19-binding domain comprises an scFv in the orientation VH-VL.

16 . The method of claim 15 , wherein the CD19-binding domain comprises the sequence shown as SEQ ID NO: 9 or a variant thereof having at least 90% sequence identity.

17 - 21 . (canceled)

22 . The method of claim 1 , wherein the CD19/22 CAR T-cell product expresses a chimeric antigen receptor (CAR) comprising a CD22-binding domain which comprises

a) a heavy chain variable region (VH) having CDRs

with the following sequences:

(SEQ ID NO: 58)

CDR1 - NFAMA;

(SEQ ID NO: 59)

CDR2 - SISTGGGNTYYRDSVKG

(SEQ ID NO: 60)

CDR3 - QRNYYDGSYDYEGYTMDA;

and

b) a light chain variable region (VL) having CDRs

with the following sequences:

(SEQ ID NO: 61)

CDR1 - RSSQDIGNYLT;

(SEQ ID NO: 62)

CDR2 - GAIKLED

(SEQ ID NO: 63)

CDR3 - LQSIQYP.

23 . The method of claim 22 , wherein the CD22-binding domain comprises a VH domain having the sequence shown as SEQ ID NO: 64 and/or or a VL domain having the sequence shown as SEQ ID NO: 65 or a variant thereof having at least 95% sequence identity.

24 . The method of claim 23 , wherein the CD22-binding domain comprises an scFv in the orientation VH-VL.

25 . The method of claim 24 , wherein the CD22-binding scFv comprises the sequence shown as SEQ ID NO: 66 or a variant thereof having at least 90% sequence identity.

26 - 30 . (canceled)

31 . The method of claim 1 , wherein the autologous CD19/22 CAR T-cells comprise a CD19/22 CAR T-cell product comprising CAT19CAR and 9A8CAR CARs.