Sequential anti-CD19 therapy

Abstract

The present invention relates to therapeutic compositions and methods for the sequential treatment of cancer in human patients with therapeutic agents that bind to human CD1g.

Description

Technical Field

[0001] The present invention relates to immunotherapeutic compositions and methods for the sequential treatment of cancer in human patients using therapeutics that bind to human CD19. Specifically, immunotherapy regimens such as CAR-T cell regimens are described, which are useful for the treatment of B-cell malignancies such as non-Hodgkin lymphoma (NHL), including diffuse large B-cell lymphoma (DLBCL), and chronic lymphocytic leukemia (CLL) in patients following a prior treatment with the anti-CD19 antibody tafasitamab.

Background Art

[0002] CD19, a co-receptor of the B-cell receptor, is a marker of the B-cell lineage as it is expressed throughout B-cell development until B cells differentiate into plasma cells (Wang, Exp Hematol Oncol. 2012). CD19 is present on the surface of both healthy and malignant B cells. Most B-cell tumors express CD19, and examples include acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), and B-cell lymphoma. Approximately 90% of diffuse large B-cell lymphoma (DLBCL) cases express the CD19 antigen (Kimura et al International Journal of Hematology 2007), and approximately 80% of ALL cases. The fact that some tumors do not express CD19 indicates that CD19 is not critical for B-cell survival. This is supported by data from CD19 knockout mice, which revealed that CD19 deficiency does not affect the number of early progenitor B cells in the bone marrow or the size and morphology of B cells. CD19− / − mice instead show a decrease in the total number and frequency of peripheral B cells. That is, CD19 contributes to the balance between humoral, antigen-induced responses and tolerance induction and thus plays a crucial role in the initiation of an optimal immune response (Wang, Exp Hematol Oncol. 2012).

[0003] Due to the ubiquitous presence of malignant B cells, CD19 is a suitable target for immunotherapy. CD19 expression is limited to cells of the B lineage and is not found in pluripotent hematopoietic stem cells or in most other normal tissues (Scheuermann, Leuk Lymphoma. 1995). Major drug classes contributing to the therapeutic drug market targeting CD19 include monoclonal antibodies (e.g., MOR208, tafasitamab; MEDI-551, inebilizumab), antibody-drug conjugates (e.g., SAR3419, coltuximab ravtansine), bispecific antibodies (e.g., blinatumomab, BLINCYTO®), or chimeric antigen receptor T cell (CAR-T) approaches (e.g., axicabtagene ciloleucel, YESCARTA®; tisagenlecleucel, KYMRIAH®).

[0004] Tafasitamab is an Fc-enhanced, humanized, monoclonal antibody targeting CD19, which has been shown to exert its anti-tumor effects through antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cell phagocytosis (ADCP), and direct cytotoxicity (Awan FT et al. Blood. 2010 Feb 11;115(6):1204-13)(WO2008022152). Tafasitamab recently received FDA breakthrough therapy designation. Currently, tafasitamab is being tested in Phase II and Phase III clinical trials in combination with the immunomodulatory agent lenalidomide (L-MIND) and the chemotherapy drug bendamustine (B-MIND) for diffuse large B-cell lymphoma (DLBCL). L-MIND (NCT02399085) is an open-label, single-arm, Phase II trial of tafasitamab (TAFA) + lenalidomide (LEN) in patients with relapsed / refractory (R / R) DLBCL who are ineligible for autologous stem cell transplantation (ASCT). B-MIND (NCT02763319) is an open-label, two-arm, Phase II / III efficacy and safety trial of tafasitamab in combination with bendamustine (BEN) compared to rituximab in patients with (R / R) DLBCL who are ineligible for high-dose chemotherapy (HDC) and ASCT.

[0005] Adoptive cell transfer using autologous T cells genetically engineered ex vivo to target tumor antigens is a promising therapeutic approach for the treatment of CD19-positive hematologic malignancies. CD19-directed chimeric antigen receptor T cell (CAR-T) therapy has shown remarkable activity in B cell lymphoma and acute lymphoblastic leukemia, and two anti-CD19 CAR-T therapies were approved by the FDA in 2017. These anti-CD19 CAR-T cells have demonstrated significant efficacy in the treatment of patients with relapsed / refractory B cell lymphoid malignancies (Maude S et al, N Engl J Med. 2018, 378:439-48), such as patients with R / R DLBCL after failure of two or more lines of systemic therapy (Neelapu S et al, N Engl J Med. 2017, 377:2531-44). Although these trials have demonstrated unprecedented efficacy, it has also become clear that not all patients respond to anti-CD19 CAR-T cells, and even patients who initially respond have limited response durations. The ability of patients to respond to CAR-T cell therapy can be affected by, for example, the number or type of prior treatment regimens, increased expression of inhibitory signals (such as PD-L1, which causes suppression) around CAR-T cells, changes in target antigen expression, or epitope loss.

[0006] Other CD19-directed modalities for the treatment of B cell malignancies, such as monoclonal antibodies and bispecific T cell engagers (BiTe), have emerged, but the issue of the appropriate treatment sequence has not yet been resolved. Therefore, it is unclear whether targeting CD19 with monoclonal antibodies such as tafasitamab interferes with the ability of CD19-targeted CAR-T to exert its antitumor effect in subsequent treatment.

[0007] The high potential of immunotherapy is generally accompanied by a warning of tumor escape, in which clonal tumor cells develop mechanisms that enable them to resist specific therapies. Among the earliest identified resistance mechanisms was the downregulation of CD19 on the surface of tumor cells (Grupp SA et al, N Engl J Med. (2013) 368:1509-18, Ruella M Comput Struct Biotechnol J. (2016) 14:357-62). Therapeutic compounds exert a selective pressure on tumors and malignant clones, but clones that have developed resistance to the therapeutic compound can proliferate. For example, CD19-negative (CD19-) relapses occur in approximately 10% to 20% of patients with acute lymphoblastic leukemia (ALL) under treatment with CD19 / CD3 bispecific T cell engagers (blinatumomab). Such immune escape can be promoted by multiple mechanisms, such as cell lineage switching, immune editing, epitope loss, splice variants or exon variants, and point mutations, including the acquisition of secondary CD19 mutations that render CD19 non-functional. Immune escape is a major form of treatment resistance in patients with ALL (Braig F et al., 2017 Blood. 129(1):100-104;Grupp SA et al. N Engl J Med. 2013 Apr 18;368(16):1509-1518). By targeting specific antigens on the surface of tumor cells with monoclonal antibodies, clones that are not recognized by the antibody or are not affected by antibody binding can be selected.

[0008] In such cases, important issues to be addressed in the era of target-directed immunotherapy are as follows: After disease progression following prior therapy against the same antigen, is it possible to target the same tumor antigen with different cancer immunotherapy modalities? In such clinical scenarios, there are concerns regarding the persistence of antigen blockade resulting from prior treatment regimens. There are also concerns regarding the selection pressure of prior therapy targeting a specific antigen enabling the outgrowth of clones that do not express the antigen, rendering subsequent therapy targeting the same target ineffective (antigen escape). Therefore, the development of novel approaches to attenuate, prevent, or eliminate escape due to antigen loss, or novel approaches that do not interfere with prior treatment regimens targeting the same antigen, would represent progress in this field.

[0009] From the prior art, it is known that CD19 can readily internalize upon Ab binding (Pulczynski S Blood. 1993, 81(6):1549-57), and loss of CD19 expression in tumor cells is a frequent escape mechanism in patients treated with CD19-targeted T cells (Grupp SA, N Engl J Med. 2013 Apr 18;368(16):1509-1518). Dual targeting by CD19 and CD123 has been described to prevent antigen-loss relapse after CD19-directed immunotherapy (Ruella et al. J Clin Invest. 2016 Oct 3;126(10):3814-3826), but this concept uses combinations of multiple targets.

[0010] The present invention is based on the surprising finding that CD19 can still be targeted after treatment with the monoclonal anti-CD19 antibody tafasitamab (MOR208). Thus, it is possible to administer another, optionally different, anti-CD19 moiety after tafasitamab treatment. Specifically, the inventors of the present disclosure surprisingly found that there is no functional interference between tafasitamab and CD19-directed CAR-T cells (CART19). This finding is supported by an unpublished case study showing durable remission in patients with relapsed and refractory DLBCL achieved by anti-CD19 CAR-T cell therapy after prior treatment with tafasitamab as part of the L-MIND clinical trial.

SUMMARY OF THE INVENTION

[0011] Disclosed are methods and compositions for treating a blood cancer, comprising administering to a patient a composition comprising autologous T cells, which express a recombinant receptor that specifically binds to an antigen specific for the blood cancer, wherein the patient has been previously treated with a composition comprising an anti-CD19 antibody, the antibody comprising i) an HCDR1 region comprising the sequence SYVMH (SEQ ID NO: 1), an HCDR2 region comprising the sequence NPYNDG (SEQ ID NO: 2), an HCDR3 region comprising the sequence GTYYYGTRVFDY (SEQ ID NO: 3), an LCDR1 region comprising the sequence RSSKSLQNVNGNTYLY (SEQ ID NO: 4), an LCDR2 region comprising the sequence RMSNLNS (SEQ ID NO: 5), and an LCDR3 region comprising the sequence MQHLEYPIT (SEQ ID NO: 6), or ii) a variable heavy chain of SEQ ID NO: 7 and a variable light chain of SEQ ID NO: 8, or iii) a heavy chain of SEQ ID NO: 11 and a light chain of SEQ ID NO: 12, or iv) tafasitamab.

[0012] More specifically, one embodiment relates to a method and a compound for treating CD19+ blood cancer. Specifically, the antigen specific to this blood cancer is human CD19. Preferably, the CD19+ blood cancer is DLBCL. In another preferred embodiment, the DLBCL is relapsed or refractory (R / R) DLBCL.

[0013] In one embodiment, the autologous T cells expressing the recombinant receptor are CAR-T cells. In one embodiment, the CAR-T cells are directed against CD20 or CD19. In a preferred embodiment, the CAR-T cells are directed against CD19. More specifically, the CAR-T cells are directed against CD19 and are selected from the group consisting of axicabtagene ciloleucel (YESCARTA™), tisagenlecleucel (KYMRIAH™), lisocabtagene maraleucel (JCAR017), and UCART19.

[0014] Specifically, CD19-directed CAR-T cells for use in cancer treatment in a patient are disclosed, where the patient has been pre-treated with an anti-CD19 antibody.

[0015] More specifically, one embodiment relates to CD19-directed CAR-T cells for use in cancer treatment in a patient who has been previously treated with a composition comprising tafasitamab. In certain embodiments, tisagenlecleucel CAR-T cells for use in cancer treatment in a patient who has been previously treated with a composition comprising tafasitamab are disclosed. Certain embodiments relate to CD19-directed CAR-T cells for use in the treatment of R / R DLBCL in a patient who has been previously treated with a composition comprising tafasitamab. Another aspect relates to CD19-directed CAR-T cells for use in the treatment of R / R DLBCL in a patient who has been previously treated with a combination therapy comprising tafasitamab and lenalidomide. In certain specific embodiments, tisagenlecleucel CAR-T cells for use in the treatment of R / R DLBCL in a patient who has been previously treated with a composition comprising tafasitamab are disclosed. In another aspect, tisagenlecleucel CAR-T cells for use in the treatment of R / R DLBCL in a patient who has been previously treated with a combination therapy comprising tafasitamab and lenalidomide are disclosed.

Brief Description of the Drawings

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Modes for Carrying Out the Invention

[0017] Definition The term "antibody" means a monoclonal antibody including any isotype, e.g., IgG, IgM, IgA, IgD, and IgE. An IgG antibody is composed of two identical heavy chains and two identical light chains, which are linked by disulfide bonds. Each heavy chain and light chain has a constant region and a variable region respectively. Each variable region has three segments called "complementary determining regions" ("CDRs") or "hypervariable regions", which are mainly responsible for binding to the epitope of an antigen. These segments are numbered in order from the N-terminus and are referred to as CDR1, CDR2, and CDR3. The more conserved portions of the variable region outside the CDRs are called "framework regions". "Antibody fragment" means an Fv, scFv, dsFv, Fab, Fab’, F(ab’)2 fragment, or other fragment, and the fragment contains at least one variable heavy chain or light chain, and each chain has a CDR and a framework region.

[0018] "VH" refers to the variable region of the immunoglobulin heavy chain of an antibody or antibody fragment. "VL" refers to the variable region of the immunoglobulin light chain of an antibody or antibody fragment.

[0019] The term "CD19" refers to the protein known as CD19, and the following synonyms exist for this term: B4, B-lymphocyte antigen CD19, B-lymphocyte surface antigen B4, CVID3, differentiation antigen CD19, MGC12802, and T-cell surface antigen Leu-12. Human CD19 (UniProt-P15391) has the following amino acid sequence: MPPPRLLFFLLFLTPMEVRPEEPLVVKVEEGDNAVLQCLKGTSDGPTQQLTWSRESPLKPFLKLSLGLPGLGIHMRPLAIWLFIFNVSQQMGGFYLCQPGPPSEKAWQPGWTVNVEGSGELFRWNVSDLGGLGCGLKNRSSEGPSSPSGKLMSPKLYVWAKDRPEIWEGEPPCLPPRDSLNQSLSQDLTMAPGSTLWLSCGVPPDSVSRGPLSWTHVHPKGPKSLLSLELKDDRPARDMWVMETGLLLPRATAQDAGKYYCHRGNLTMSFHLEITARPVLWHWLLRTGGWKVSAVTLAYLIFCLCSLVGILHLQRALVLRRKRKRMTDPTRRFFKVTPPPGSGPQNQYGNVLSLPTPTSGLGRAQRWAAGLGGTAPSYGNPSSDVQADGALGSRSPPGVGPEEEEGEGYEEPDSEEDSEFYENDSNLGQDQLSQDGSGYENPEDEPLGPEDEDSFSNAESYENEDEELTQPVARTMDFLSPHGSAWDPSREATSLGSQSYEDMRGILYAAPQLRSIRGQPGPNHEEDADSYENMDNPDGPDPAWGGGGRMGTWSTR (SEQ ID NO: 13). Variants of human CD19 (e.g., splice variants, gene polymorphisms, and SNPs) are also encompassed by this application.

[0020] "MOR00208", "MOR208", "XmAb5574", or "tafasitamab" is an anti-CD19 antibody. The amino acid sequences of the VH and VL domains are shown in SEQ ID NOs: 7 and 8, respectively. The amino acid sequence of the MOR208 heavy chain Fc region is as follows: ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPDVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTFRVVSVLTVVHQDWLNGKEYKCKVSNKALPAPEEKTISKTKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO:9). The amino acid sequence of the light chain Fc region of MOR208 is as follows: RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO:10). The MOR208 antibody is described in U.S. Patent Application No. 12 / 377,251 (which is hereby incorporated by reference in its entirety) as an antibody named 4G7 H1.52 Hybrid S239D / I332E / 4G7 L1.155 (subsequently named MOR00208), and the sequence is as follows: >4G7 H1.52 Hybrid S239D / I332E EVQLVESGGGLVKPGGSLKLSCAASGYTFTSYVMHWVRQAPGKGLEWIGYINPYNDGTKYNEKFQGRVTISSDKSISTAYMELSSLRSEDTAMYYCARGTYYYGTRVFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPDVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTFRVVSVLTVVHQDWLNGKEYKCKVSNKALPAPEEKTISKTKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 11) >4G7 L1.155 DIVMTQSPATLSLSPGERATLSCRSSKSLQNVNGNTYLYWFQQKPGQSPQLLIYRMSNLNSGVPDRFSGSGSGTEFTLTISSLEPEDFAVYYCMQHLEYPITFGAGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 12)

[0021] "Administered" or "administration" includes, but is not limited to, drug delivery by an injectable form, e.g., by intravenous, intramuscular, intradermal, or subcutaneous routes, or by mucosal routes, e.g., as a nasal spray or inhalation aerosol, or as an orally ingestible solution, capsule, or tablet. Preferably, administration is by an injectable form.

[0022] The term "chimeric antigen receptor (CAR)", as used herein, can refer to, for example, a modified T cell receptor, a chimeric T cell receptor, or a chimeric immune receptor, and can include a modified receptor that conjugates a defined specificity onto a particular immune effector cell. By using a CAR, the specificity of a monoclonal antibody can be conferred on T cells, thereby enabling the generation of a large number of specific T cells for use, for example, in adoptive cell therapy. In a specific embodiment, the CAR directs the specificity of the cell, for example, to a tumor-associated antigen. In some embodiments, the CAR includes an extracellular domain including an intracellular activation domain, a transmembrane domain, and a tumor-associated antigen binding region. In some aspects, the CAR includes a fusion in which the FMC63 single-chain variable fragment (scFv) derived from a monoclonal antibody is fused to the hinge linker CD8h, the transmembrane domain CD8TM, and the signaling end domain 41BBζ. The specificity of CAR design may be derived from an antibody fragment (e.g., scFv, Fab, VHH, scFab), a ligand of a receptor (e.g., a peptide), or a dectin. In a specific embodiment, by using a CAR specific for a B cell lineage molecule, CD19, the specificity of T cells can be redirected to target malignant B cells. In certain cases, the CAR includes an additional co-stimulatory signaling domain, which domains include, for example, but are not limited to, CD3ζ, FcR, CD27, CD28, CD137, DAP10, 41BBζ, and / or OX40. In some cases, a molecule can be co-expressed with the CAR, and such molecules include co-stimulatory molecules, reporter genes for imaging (e.g., for positron emission tomography), gene products that conditionally excise T cells upon addition of a prodrug, homing receptors, cytokines, and cytokine receptors.

[0023] A "therapeutically effective amount" of a compound or combination thereof refers to an amount sufficient to cure, alleviate, or partially arrest the clinical condition of a given disease or disorder and its complications. The amount effective for a particular therapeutic purpose will depend on the severity of the disease or injury, as well as the body weight and general condition of the subject. Of course, determination of the appropriate dosage can be accomplished by constructing a matrix of values and testing at different points in the matrix using routine experimentation, all of which are within the ordinary skill of a skilled physician or clinical scientist.

[0024] The term "blood cancer" includes blood-derived tumors and diseases or disorders in which abnormal cell growth and / or proliferation in tissues of hematopoietic origin is involved, such as lymphomas, leukemias, and myelomas.

[0025] Non-Hodgkin lymphoma (NHL) is a heterogeneous malignancy that originates from lymphocytes. In the United States, its incidence is estimated at 65,000 cases / year, and the number of deaths is approximately 20,000 (American Cancer Society, 2006; and SEER Cancer Statistics Review). This disease can occur at all ages, but the typical onset begins in adults over 40 years old, and the incidence increases with age. NHL is characterized by the clonal expansion of lymphocytes that accumulate in lymph nodes, blood, bone marrow, and spleen, but any major organ can be involved. The current classification system used by pathologists and physicians is the World Health Organization (WHO) tumor classification, which organizes NHL into precursor and mature B-cell or T-cell neoplasms. PDQ currently divides NHL into indolent or aggressive for participation in clinical trials. The indolent NHL group mainly consists of follicular subtypes, small lymphocytic lymphoma, MALT (mucosa-associated lymphoid tissue), and marginal zone; indolent accounts for approximately 50% of newly diagnosed B-cell NHL patients. Aggressive NHL includes patients with a histological diagnosis of primary diffuse large B-cell lymphoma (DLBL, "DLBCL", or DLCL) (40% of all newly diagnosed patients have diffuse large B-cell lymphoma), Burkitt, and mantle cell lymphoma ("MCL"). The most commonly used agents in combination chemotherapy are cyclophosphamide, vincristine, and prednisone (CVP); or cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP). Approximately 70% - 80% of patients respond to their first chemotherapy, and the remission period lasts about 2 - 3 years. Eventually, most patients relapse. The discovery and clinical use of rituximab, an anti-CD20 antibody, have brought significant improvements in response and survival rates. The current standard treatment for most patients is rituximab + CHOP (R-CHOP) or rituximab + CVP (R-CVP).Rituximab therapy has been shown to be effective in multiple types of NHL and is currently approved as a first-line treatment for both indolent (follicular lymphoma) and aggressive NHL (diffuse large B-cell lymphoma). However, anti-CD20 monoclonal antibodies (mAbs) have significant limitations, including primary resistance (50% response in relapsed indolent patients), acquired resistance (50% response rate upon retreatment), rare complete responses (2% complete response rate in the relapsed population), and a continuous pattern of relapse. Finally, many B cells do not express CD20, and thus many B-cell disorders cannot be treated with anti-CD20 antibody therapy.

[0026] Chronic lymphocytic leukemia (CLL) (also known as "chronic lymphoid leukemia" or "CLL") is a type of adult leukemia caused by the abnormal accumulation of B lymphocytes. In CLL, the malignant lymphocytes may appear normal and mature, but they are unable to effectively combat infections. CLL is the most common form of leukemia in adults. Men are twice as likely as women to develop CLL. However, the most important risk factor is age. More than 75% of new cases are diagnosed in patients over 50 years old. More than 10,000 cases are diagnosed each year, and the mortality rate is approximately 5,000 cases per year (American Cancer Society, 2006; and SEER Cancer Statistics Review). CLL is an incurable disease, but its progression is slow in most cases. Many people with CLL lead normal and active lives for many years. Because its onset is slow, early-stage CLL is generally not treated. This is because it is thought that early CLL intervention does not improve either survival or quality of life. Instead, the condition is monitored over time. Early CLL treatment varies according to the accurate diagnosis and the progression of the disease. There are numerous agents used in CLL treatment. Combination chemotherapy regimens, such as FCR (fludarabine, cyclophosphamide, and rituximab), and BR (ibrutinib and rituximab), are effective for both newly diagnosed CLL and relapsed CLL. Allogeneic bone marrow (stem cell) transplantation is rarely used as a first-line treatment because of its risks.

[0027] Another type of leukemia is small lymphocytic lymphoma (''SLL''), which lacks the clonal lymphocytosis required for a CLL diagnosis but is otherwise considered a variant of CLL with common pathologic and immunophenotypic features (Campo et al., 2011). The definition of SLL requires the presence of lymphadenopathy and / or splenomegaly. Moreover, the number of B lymphocytes in the peripheral blood should not exceed 5E+09 / L. In SLL, the diagnosis must be confirmed, whenever possible, by histopathological evaluation of a lymph node biopsy (Hallek et al., 2008). The incidence of SLL is approximately 25% of CLL in the United States (Dores et al., 2007).

[0028] Another type of leukemia is acute lymphoblastic leukemia (ALL), also known as acute lymphocytic leukemia. ALL is characterized by the overproduction and continuous proliferation of malignant and immature white blood cells (also known as lymphoblasts) in the bone marrow. The term ''acute'' indicates that the circulating lymphocytes (''blasts'') are undifferentiated and immature and that the disease progresses rapidly, with a median survival of a few weeks to months if left untreated.

[0029] ''Subject'' or ''patient'', as used in this context, refers to any mammal, including, but not limited to, rodents such as mice or rats, and primates such as cynomolgus monkeys (Macaca fascicularis), rhesus monkeys (Macaca mulatta), or humans (Homo sapiens). Preferably, the subject or patient is a primate, and most preferably a human.

[0030] The term "co-administration" or "pharmaceutical co-administration" refers to the administration of one treatment in addition to another. Thus, "in co-administration with" includes simultaneous (e.g., concurrent) and sequential administration in any order. By way of non-limiting example, a first treatment (e.g., an agent such as an anti-CD19 antibody) can be administered to a patient before (e.g., 1 minute, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, or 12 weeks before), simultaneously with, or after (e.g., 1 minute, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, or 12 weeks, or more thereafter) the administration of a second treatment (e.g., a pharmaceutical agent such as lenalidomide).

[0031] The term "sequential co-administration" or "sequential treatment co-administration" refers to the administration of a different treatment after a prior treatment has been completed. An additional treatment can be included between the two treatments. By way of example and as an embodiment disclosed herein, sequential co-administration refers to treating a patient with chimeric antigen receptor (CAR) T cells directed to CD19 after the patient has relapsed from a prior treatment comprising an anti-CD19 antibody as disclosed herein or when the patient is treatment resistant to such prior treatment. In certain embodiments, the prior treatment or first treatment of the sequential co-administration is completed 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, or 12 weeks, or more before the administration of the second, different treatment.

[0032] Examples of "thalidomide analogs" include, but are not limited to, thalidomide itself, lenalidomide (CC-5013, Revlimid™), pomalidomide (CC4047, Actimid™), and the compounds disclosed in WO2002068414 and WO2005016326, which are incorporated herein by reference in their entireties. This term refers to chemically synthesized compounds that use the thalidomide structure as a backbone (e.g., those with side chains added or such groups removed from the parent structure). Analogs differ structurally from thalidomide and its metabolite compounds, for example, in the length of the alkyl chain, molecular fragments, one or more functional groups, or differences in charge upon ionization. The term "thalidomide analogs" includes metabolites of thalidomide. Thalidomide analogs include racemic mixtures of the S and R enantiomers of each compound, as well as the individual S or R enantiomers. Racemic mixtures are preferred. Thalidomide analogs include compounds such as lenalidomide, which has the following structure: [Chemical Formula]

[0033] As used herein, the term "relapse" refers to, for example, the reappearance of a disease (e.g., cancer) after a prior treatment with a certain therapy, such as during the initial response period (e.g., complete or partial response) after cancer treatment. More generally, in certain embodiments, a response (e.g., complete or partial response) may involve the absence of detectable minimal residual disease (MRD). In certain embodiments, the initial response period lasts at least 1, 2, 3, 4, 5, or 6 days; at least 1, 2, 3, or 4 weeks; at least 1, 2, 3, 4, 6, 8, 10, or 12 months; or at least 1, 2, 3, 4, or 5 years.

[0034] "Refractory", as used herein, refers to a disease that does not respond to treatment, such as cancer. In multiple embodiments, refractory cancer may be resistant to treatment from before treatment or at the start of treatment. In other embodiments, refractory cancer may become resistant during treatment. Refractory cancer is also referred to as resistant cancer.

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[0035] In various aspects, the present invention relates to a nucleic acid sequence encoding either the disclosed antibody or CAR for use in the treatment of cancer in a patient as described herein.

Examples

[0036] The CART19 cells used in the experiment were generated by lentivirally transducing healthy donor T cells using a second-generation CD19 CAR construct (clone FMC63 as the CD19 binding domain, FMC63-CD8h-CD8TM-41BBζ, similar to the FDA-approved construct used in tisagenlecleucel). T cells isolated from normal donors were stimulated using Cell Therapy Systems Dynabeads CD3 / CD28 (Life Technologies, Oslo, Norway) at a ratio of 1:3 (cells:beads), and then, 24 hours after stimulation, were transduced using lentiviral particles at an MOI of 3.0. On day 6, magnetic beads were removed and the CAR19 expression of the T cells was evaluated by flow cytometry. On day 8, the CART cells were collected and cryopreserved for future experiments. The CART cells were thawed and placed in T cell medium 6 - 12 hours before using them in the experiment, as specified for each experiment.

[0037] Example 1 The functional activities of tafasitamab or CART19 cells were tested in CD19-positive target cell lines, Jeko (mantle cell lymphoma), Ly7 (DLBCL), and Nalm-6 (ALL). The cell lines were originally obtained from ATCC or DSMZ. The cell lines were transduced with luciferase (firefly / EGFP, CBG / EGFP, or CBR / EGFP) and then sorted to obtain a population with over 99% positivity. In the 24-hour ADCC assay (increasing tafasitamab + natural killer (NK) cells; Figure 1) and T cell cytotoxicity assay (CART19, E:T increasing; data not shown), clear activity was observed for both treatments in all cell lines tested. The killing assay was performed according to the standard protocol (Cao L-F et al. Cytometry A, 2010, vol. 77 6 (pg.534-545)). Briefly, cytotoxicity was evaluated 24 hours after incubation with various concentrations of tafasitamab added to CD19+ luciferase+ target cells in the presence or absence of NK cells.

[0038] Example 2 It was investigated whether the observed CART19 activity might be affected by tocilizumab in the case of a direct CD19 binding competition between tocilizumab and the CAR. First, to test for such a binding competition, the CD19+ cell lines Nalm-6 or Jeko were incubated with 2 or 0.5 mg / mL of tocilizumab to saturate the receptor. In subsequent flow cytometry analysis using the FMC63 antibody (which has the same CD19 binding domain as CART19), no CD19 expression could be detected, indicating a direct binding competition between FMC63 and tocilizumab (Figure 2). To investigate whether there was any potential impact of such a binding competition on CART19 cell effector function, tocilizumab was incubated with target cells (CD19+ cell lines, Jeko, Ly7, or Nalm-6) at increasing concentrations, and then CART19 cells were added at different effector:target ratios (0.1:1 to 10:1), and no other effector cells were added to the cell culture. The presence of tocilizumab, i.e., its binding to the CD19 antigen, did not affect important CART cell effector functions such as antigen-specific killing (Figure 3), degranulation (Figure 4), cytokine production by CART19 cells, or antigen-specific proliferation (Figure 5).

[0039] In summary, the data indicate that CART19 cells continue to exhibit strong antigen-specific effector functions despite the presence of tocilizumab and the competition regarding its CD19 binding. That is, targeting CD19 with tocilizumab does not impair CD19-directed chimeric antigen receptor (CAR) T cell activity in vitro.

[0040] Example 3 In a case study of a 58-year-old female patient who initially had an 8-cm mesenteric tumor, a stage III germinal center B-cell-like (GCB) DLBCL arising from follicular lymphoma, a Ki-67 proliferation index of 80%, and an IGH / BCL2 fusion were revealed from a detailed examination. The patient was administered dose-adjusted R-EPOCH in 6 cycles. Although a complete remission (CR) was achieved with this cutting-edge treatment, the patient experienced recurrence within 2 years. Subsequently, the patient received rituximab + ifosfamide, carboplatin, and etoposide (RICE) chemotherapy, which achieved a second CR. The patient refused ASCT. The second recurrence occurred approximately 2 years later. After meeting the eligibility criteria, the patient was enrolled in the L-MIND clinical trial and received 6 cycles of TAFA+LEN (1 cycle = 28 days; TAFA at 12 mg / kg intravenously, once a week for 3 cycles and then once every 2 weeks; LEN at 25 mg daily, on days 1 to 21 of each cycle). TAFA / LEN was well tolerated. Disease stabilization was achieved with this trial regimen but progression occurred 6 months later. The fourth treatment consisted of administering 4 cycles of rituximab, gemcitabine, oxaliplatin, (R-GEM-OX), to which the patient showed a partial response. Shortly thereafter, the patient received CD19-directed CART therapy (axicabtagene ciloleucel [YESCARTA®]) (Figure 6). The treatment course was complicated by grade 2 cytokine release syndrome. Complete response was achieved 1 month after treatment and has since been maintained. At the time of the current data, the patient remains without clinical evidence of recurrence. That is, in patients with relapsed and refractory diffuse large B-cell lymphoma (R / R-DLBCL), durable remission has been achieved with CD19-directed CAR-T cell therapy regardless of prior treatment with tafasitamab.

[0041] The half-life of tafasitamab is approximately 16 days, suggesting that tafasitamab was eliminated before CART cell infusion 5 months later. Although biopsies were not performed during the progression after TAFA, CD19 antigen escape is not thought to have been the main cause of recurrence because the patient achieved sustained remission with subsequent CD19-directed CART therapy. Therefore, just because the disease progressed after treatment with the anti-CD19 monoclonal antibody tafasitamab does not preclude the patient from CD19-directed CAR-T therapy, whether or not the same antigen was targeted previously.

[0042] Example 4 - On day -14, 1×10 6 luciferase+JeKo-1 cells were injected into NSG (NOD scid gamma mice, immunodeficient experimental mice) mice. On day -8, the tumor volume was evaluated by bioluminescence imaging (BLI), and the mice were randomly divided into a tafasitamab group (10 mice) and a PBS group (4 mice). The tafasitamab group was administered tafasitamab by ip injection at 10 mg / kg three times a week. On day -1, the tumor volume was evaluated by BLI, and the mice were randomly divided into a tafasitamab continuation or tafasitamab discontinuation group. On day 0, 2.5×10 6 CART19 cells were administered (IV) to all mice in the three groups. Mice in the tafasitamab continuation group continued tafasitamab treatment in parallel with CART19 cells. For all mice, BLI was performed weekly to monitor the tumor volume, and the survival of the mice was monitored. The mice were sacrificed.

[0043] CD19 competition was observed in the tafasitamab continuation group, and it was demonstrated that the survival period was shortened (p = 0.005, log-rank test, continuation vs discontinuation or continuation vs PBS). However, in the tafasitamab discontinuation group, remission was induced in the mice, and no decrease in the survival period was observed. Overall and with respect to overall survival, there was no difference between the PBS group and the tafasitamab discontinuation group (log-rank test) (Figure 7).

[0044] Furthermore, the tofacitinib continuation group showed a higher tumor burden compared to the discontinuation group or the PBS control group ( **** p < 0.0001, two-way ANOVA, continuation vs. discontinuation or continuation vs. PBS). No difference was observed between the tofacitinib discontinuation group and the PBS group (n.s., not significant, two-way ANOVA, discontinuation vs. PBS) (Figure 8).

[0045] Therefore, these in vivo data indicate that CD19-directed CAR-T cell therapy is not impaired by prior tofacitinib treatment. It can be concluded that prior tofacitinib treatment does not exclude patients from CD19-directed CAR-T cell therapy.

[0046] However, these data also show that if the CD19 antibody and CD19 CART compete for the same or overlapping CD19 epitopes, the combination parallel treatment of the CD19 antibody and CD19-directed CAR-T cell therapy may have a negative impact on the efficacy of the therapy.

[0047] Embodiments In one embodiment, a CD19-directed therapeutic agent for use in treating cancer in a patient is disclosed, wherein the patient has been previously treated with a composition comprising an anti-CD19 antibody, and the antibody has an HCDR1 region comprising the sequence SYVMH (SEQ ID NO: 1), an HCDR2 region comprising the sequence NPYNDG (SEQ ID NO: 2), an HCDR3 region comprising the sequence GTYYYGTRVFDY (SEQ ID NO: 3), an LCDR1 region comprising the sequence RSSKSLQNVNGNTYLY (SEQ ID NO: 4), an LCDR2 region comprising the sequence RMSNLNS (SEQ ID NO: 5), and an LCDR3 region comprising the sequence MQHLEYPIT (SEQ ID NO: 6).

[0048] In one aspect, a CD19-directed therapeutic agent for use in treating cancer in a patient is disclosed, where the patient is treatment-resistant to or has experienced recurrence from a prior treatment that included an anti-CD19 antibody having an HCDR1 region comprising the sequence SYVMH (SEQ ID NO: 1), an HCDR2 region comprising the sequence NPYNDG (SEQ ID NO: 2), an HCDR3 region comprising the sequence GTYYYGTRVFDY (SEQ ID NO: 3), an LCDR1 region comprising the sequence RSSKSLQNVNGNTYLY (SEQ ID NO: 4), an LCDR2 region comprising the sequence RMSNLNS (SEQ ID NO: 5), and an LCDR3 region comprising the sequence MQHLEYPIT (SEQ ID NO: 6).

[0049] In another embodiment, a CD19-directed therapeutic agent for use in treating cancer in a patient is disclosed, where the patient is treatment-resistant to or has experienced recurrence from a prior treatment that included a variable heavy chain comprising the sequence EVQLVESGGGLVKPGGSLKLSCAASGYTFTSYVMHWVRQAPGKGLEWIGYINPYNDGTKYNEKFQGRVTISSDKSISTAYMELSSLRSEDTAMYYCARGTYYYGTRVFDYWGQGTLVTVSS (SEQ ID NO: 7) and / or a variable light chain comprising the sequence DIVMTQSPATLSLSPGERATLSCRSSKSLQNVNGNTYLYWFQQKPGQSPQLLIYRMSNLNSGVPDRFSGSGSGTEFTLTISSLEPEDFAVYYCMQHLEYPITFGAGTKLEIK (SEQ ID NO: 8) of an anti-CD19 antibody.

[0050] In one embodiment, a CD19-directed therapeutic agent for use in treating cancer in a patient is disclosed, where the patient is treatment-resistant to or has experienced a recurrence with respect to a prior treatment that included an anti-CD19 antibody having a variable heavy chain of SEQ ID NO: 7 and / or a variable light chain of SEQ ID NO: 8 and having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with the variable heavy chain and / or variable light chain.

[0051] In a preferred embodiment, a CD19-directed therapeutic agent for use in treating cancer in a patient is disclosed, where the patient is treatment-resistant to or has experienced a recurrence with respect to a prior treatment that included an anti-CD19 antibody having a heavy chain of SEQ ID NO: 11 and a light chain of SEQ ID NO: 12.

[0052] In another preferred embodiment, a CD19-directed therapeutic agent for use in treating cancer in a patient is disclosed, where the patient is treatment-resistant to or has experienced a recurrence with respect to a prior treatment that included the anti-CD19 antibody tafasitamab.

[0053] In another embodiment, a CD19-directed therapeutic agent for use in treating cancer in a patient is disclosed, where the patient is treatment-resistant to or has experienced a recurrence with respect to a prior treatment that included an anti-CD19 antibody that competes with the CD19-directed therapeutic agent with respect to binding to human CD19.

[0054] In other embodiments, a CD19-directed therapeutic agent for use in treating cancer in a patient is disclosed, where the patient is treatment-resistant to or has experienced a recurrence with respect to a prior treatment that included an anti-CD19 antibody, and the CD19-directed therapeutic agent is selected from the group consisting of an antibody, an antibody-drug conjugate, a bispecific antibody, an alternative scaffold protein, or a chimeric antigen receptor (CAR) T cell.

[0055] In a preferred embodiment, a therapeutic agent directed to CD19 for use in treating cancer in a patient who is treatment resistant or has relapsed to a prior treatment comprising an anti-CD19 antibody is a chimeric antigen receptor (CAR) T cell. In certain embodiments, the CAR-T cells are preferably axicabtagene ciloleucel (KTE-C19, Axi-cel, YESCARTA®) and / or tisagenlecleucel (CTL019, KYMRIAH®), lisocabtagene maraleucel (JCAR017, clinical trials: e.g., NCT02631044, NCT03310619), or UCART19 (S68587, NCT02808442), or a combination of two or more of these. In another aspect, the CAR-T cells are one of the CAR-T cell constructs known as KITE037, welgenaleucel, ICTCAR-003, IM-19, CTX-110, SSCAR-010, ICTCAR-011, or a combination of two or more of these.

[0056] In other embodiments, the therapeutic agent for use in treating cancer in a patient who is treatment resistant or has relapsed to a prior treatment comprising an anti-CD19 antibody is directed to a B cell lineage marker. Preferably, the therapeutic agent for use in treating cancer in a patient is directed to CD19 and / or CD20, and the patient is treatment resistant or has relapsed to a prior treatment comprising the anti-CD19 antibody tafasitamab.

[0057] In another embodiment, the CAR-T cells for use in treating cancer in a patient are directed to CD19 and / or CD20, and the patient is treatment resistant or has relapsed to a prior treatment comprising the anti-CD19 antibody tafasitamab.

[0058] In a preferred embodiment, the therapeutic agent is for use in a pharmaceutical composition. In other embodiments, the therapeutic agent is included in a pharmaceutical composition.

[0059] In one aspect, a CD19-directed therapeutic agent for use in treating cancer in a patient is disclosed, where the patient is treatment-resistant or has relapsed to a prior treatment, the prior treatment includes an anti-CD19 antibody, and the cancer is a blood cancer. In certain embodiments, the blood cancer is selected from non-Hodgkin B-cell lymphoma, such as follicular lymphoma (FL), small lymphocytic lymphoma (SLL), Burkitt lymphoma, and diffuse large B-cell lymphoma (DLBCL), Waldenström macroglobulinemia, leukemia, such as chronic lymphocytic leukemia (CLL), acute lymphoblastic leukemia (ALL), or acute myeloid leukemia (AML). In a preferred embodiment, the blood cancer is DLBCL. In other embodiments, the cancer is a relapsed or refractory (R / R) cancer, preferably a relapsed or refractory blood cancer. R / R blood cancers are selected from R / R non-Hodgkin B-cell lymphoma, such as R / R follicular lymphoma (FL), R / R small lymphocytic lymphoma (SLL), R / R Burkitt lymphoma, and R / R diffuse large B-cell lymphoma (DLBCL), R / R Waldenström macroglobulinemia, R / R leukemia, such as R / R chronic lymphocytic leukemia (CLL), R / R acute lymphoblastic leukemia (ALL), or R / R acute myeloid leukemia (AML). In a preferred embodiment, the R / R blood cancer is relapsed or refractory (R / R) diffuse large B-cell lymphoma (DLBCL).

[0060] In certain embodiments, a CD19-directed CAR-T cell for use in treating R / R DLBCL in a patient is disclosed, where the patient is treatment-resistant or has relapsed to a prior treatment, the prior treatment includes an anti-CD19 antibody, preferably an antibody having the following i) An HCDR1 region comprising the sequence SYVMH (SEQ ID NO: 1), an HCDR2 region comprising the sequence NPYNDG (SEQ ID NO: 2), an HCDR3 region comprising the sequence GTYYYGTRVFDY (SEQ ID NO: 3), an LCDR1 region comprising the sequence RSSKSLQNVNGNTYLY (SEQ ID NO: 4), an LCDR2 region comprising the sequence RMSNLNS (SEQ ID NO: 5), and an LCDR3 region comprising the sequence MQHLEYPIT (SEQ ID NO: 6), or ii) A variable heavy chain of SEQ ID NO: 7 and a variable light chain of SEQ ID NO: 8, or iii) A heavy chain of SEQ ID NO: 11 and a light chain of SEQ ID NO: 12, or iv) Tafasitamab.

[0061] In certain embodiments, CD19-directed CAR-T cells for use in treating R / R DLBCL in a patient are disclosed, where the patient is treatment resistant or has relapsed to a prior treatment that includes the combination of tafasitamab and lenalidomide.

[0062] In another embodiment, CD19-directed CAR-T cells for use in treating R / R DLBCL in a patient are disclosed, where the patient is treatment resistant or has relapsed to a prior treatment that includes the combination of tafasitamab and bendamustine.

[0063] In one aspect, an anti-CD19 antibody is disclosed for use in treating cancer in a patient, where the patient is treated with CD19-directed CAR-T cells after treatment with the anti-CD19 antibody, and the anti-CD19 antibody has an HCDR1 region comprising the sequence SYVMH (SEQ ID NO: 1), an HCDR2 region comprising the sequence NPYNDG (SEQ ID NO: 2), an HCDR3 region comprising the sequence GTYYYGTRVFDY (SEQ ID NO: 3), an LCDR1 region comprising the sequence RSSKSLQNVNGNTYLY (SEQ ID NO: 4), an LCDR2 region comprising the sequence RMSNLNS (SEQ ID NO: 5), and an LCDR3 region comprising the sequence MQHLEYPIT (SEQ ID NO: 6).

[0064] In one aspect, for use in treating cancer in a patient, an anti-CD19 antibody is disclosed herein, the patient is treated with CD19-directed CAR-T cells after treatment with the anti-CD19 antibody, and this anti-CD19 antibody has a variable heavy chain of SEQ ID NO: 7 and a variable light chain of SEQ ID NO: 8.

[0065] In one aspect, for use in treating cancer in a patient, an anti-CD19 antibody is disclosed herein, the patient is treated with CD19-directed CAR-T cells after treatment with the anti-CD19 antibody, and this anti-CD19 antibody has a heavy chain of SEQ ID NO: 11 and a light chain of SEQ ID NO: 12.

[0066] In certain aspects, for use in treating cancer in a patient, an anti-CD19 antibody is disclosed herein, the patient is treated with CD19-directed CAR-T cells after treatment with the anti-CD19 antibody, and this anti-CD19 antibody comprises tafasitamab.

[0067] In one aspect, for use in treating cancer in a patient, an anti-CD19 antibody is disclosed herein, the patient is treatment-resistant or has relapsed after treatment with the anti-CD19 antibody and is treated with CD19-directed CAR-T cells, and this anti-CD19 antibody has an HCDR1 region comprising the sequence SYVMH (SEQ ID NO: 1), an HCDR2 region comprising the sequence NPYNDG (SEQ ID NO: 2), an HCDR3 region comprising the sequence GTYYYGTRVFDY (SEQ ID NO: 3), an LCDR1 region comprising the sequence RSSKSLQNVNGNTYLY (SEQ ID NO: 4), an LCDR2 region comprising the sequence RMSNLNS (SEQ ID NO: 5), and an LCDR3 region comprising the sequence MQHLEYPIT (SEQ ID NO: 6).

[0068] In one aspect, for use in treating cancer in a patient, an anti-CD19 antibody is disclosed herein, the patient is treatment-resistant or has relapsed after treatment with the anti-CD19 antibody and is treated with CD19-directed CAR-T cells, and this anti-CD19 antibody has a variable heavy chain of SEQ ID NO: 7 and a variable light chain of SEQ ID NO: 8.

[0069] In one embodiment, an anti-CD19 antibody is disclosed herein for use in treating cancer in a patient, the patient is treatment resistant or has relapsed after treatment with the anti-CD19 antibody, and has been treated with CD19-directed CAR-T cells, and the anti-CD19 antibody has a heavy chain of SEQ ID NO: 11 and a light chain of SEQ ID NO: 12.

[0070] In certain embodiments, an anti-CD19 antibody is disclosed herein for use in treating cancer in a patient, the patient is treatment resistant or has relapsed after treatment with the anti-CD19 antibody, and has been treated with CD19-directed CAR-T cells, and the anti-CD19 antibody comprises tafasitamab.

[0071] In one embodiment, an anti-CD19 antibody is disclosed herein for use in treating cancer in a patient, the patient is treatment resistant or has relapsed after treatment with the anti-CD19 antibody in combination with lenalidomide or bendamustine, and has been treated with CD19-directed CAR-T cells, and the anti-CD19 antibody has an HCDR1 region comprising the sequence SYVMH (SEQ ID NO: 1), an HCDR2 region comprising the sequence NPYNDG (SEQ ID NO: 2), an HCDR3 region comprising the sequence GTYYYGTRVFDY (SEQ ID NO: 3), an LCDR1 region comprising the sequence RSSKSLQNVNGNTYLY (SEQ ID NO: 4), an LCDR2 region comprising the sequence RMSNLNS (SEQ ID NO: 5), and an LCDR3 region comprising the sequence MQHLEYPIT (SEQ ID NO: 6).

[0072] In one embodiment, an anti-CD19 antibody is disclosed herein for use in treating cancer in a patient, the patient is treatment resistant or has relapsed after treatment with the anti-CD19 antibody in combination with lenalidomide or bendamustine, and has been treated with CD19-directed CAR-T cells, and the anti-CD19 antibody has a variable heavy chain of SEQ ID NO: 7 and a variable light chain of SEQ ID NO: 8.

[0073] In one aspect, for use in treating cancer in a patient, an anti-CD19 antibody is disclosed herein, the patient is treatment-resistant or has relapsed after treatment with the anti-CD19 antibody in combination with lenalidomide or bendamustine, and has been treated with CD19-directed CAR-T cells, and this anti-CD19 antibody has a heavy chain of SEQ ID NO: 11 and a light chain of SEQ ID NO: 12.

[0074] In certain aspects, for use in treating cancer in a patient, an anti-CD19 antibody is disclosed herein, the patient is treatment-resistant or has relapsed after treatment with the anti-CD19 antibody in combination with lenalidomide or bendamustine, and has been treated with CD19-directed CAR-T cells, and this anti-CD19 antibody comprises tafasitamab.

[0075] In one aspect, for use in treating cancer in a patient, an anti-CD19 antibody is disclosed herein, the patient is treatment-resistant or has relapsed after anti-CD19 antibody treatment, and has been treated with CD19-directed CAR-T cells, and this anti-CD19 antibody has an HCDR1 region comprising the sequence SYVMH (SEQ ID NO: 1), an HCDR2 region comprising the sequence NPYNDG (SEQ ID NO: 2), an HCDR3 region comprising the sequence GTYYYGTRVFDY (SEQ ID NO: 3), an LCDR1 region comprising the sequence RSSKSLQNVNGNTYLY (SEQ ID NO: 4), an LCDR2 region comprising the sequence RMSNLNS (SEQ ID NO: 5), and an LCDR3 region comprising the sequence MQHLEYPIT (SEQ ID NO: 6), and this CD19-directed CAR-T cell comprises one of axicabtagene ciloleucel (YESCARTA®) and / or tisagenlecleucel (KYMRIAH®), lisocabtagene maraleucel (JCAR017), or UCART19 (S68587), or a combination of two or more of these.

[0076] In one aspect, an anti-CD19 antibody is disclosed herein for use in treating cancer in a patient who is treatment resistant or has relapsed after treatment with the anti-CD19 antibody and has been treated with CD19-directed CAR-T cells, and this anti-CD19 antibody has a variable heavy chain of SEQ ID NO: 7 and a variable light chain of SEQ ID NO: 8, and this CD19-directed CAR-T cell comprises axicabtagene ciloleucel (YESCARTA®) and / or tisagenlecleucel (KYMRIAH®), lisocabtagene maraleucel (JCAR017), or UCART19 (S68587), or a combination of two or more thereof.

[0077] In one aspect, an anti-CD19 antibody is disclosed herein for use in treating cancer in a patient who is treatment resistant or has relapsed after treatment with the anti-CD19 antibody and has been treated with CD19-directed CAR-T cells, and this anti-CD19 antibody has a heavy chain of SEQ ID NO: 11 and a light chain of SEQ ID NO: 12, and this CD19-directed CAR-T cell comprises axicabtagene ciloleucel (YESCARTA®) and / or tisagenlecleucel (KYMRIAH®), lisocabtagene maraleucel (JCAR017), or UCART19 (S68587), or a combination of two or more thereof.

[0078] In certain embodiments, anti-CD19 antibodies are disclosed herein for use in treating cancer in a patient who is treatment resistant or has relapsed after treatment with the anti-CD19 antibody, and who has been treated with CD19-directed CAR-T cells, and wherein the anti-CD19 antibody comprises tafasitamab, and wherein the CD19-directed CAR-T cells comprise axicabtagene ciloleucel (YESCARTA®) and / or tisagenlecleucel (KYMRIAH®), lisocabtagene maraleucel (JCAR017), or UCART19 (S68587), or a combination of two or more thereof.

[0079] In other embodiments, the CAR-T cells are one of the CAR-T cell constructs known as KITE037, welgenaleucel, ICTCAR-003, IM-19, CTX-110, SSCAR-010, ICTCAR-011, or a combination of two or more thereof.

[0080] In another embodiment, a sequential combination therapy is disclosed that comprises an anti-CD19 antibody and CD19-directed chimeric antigen receptor (CAR) T cells for use in treating cancer.

[0081] In certain embodiments, a sequential combination therapy is disclosed that comprises an anti-CD19 antibody and CD19-directed CAR-T cells for use in treating cancer, wherein the anti-CD19 antibody is administered to a cancer patient, and wherein the CD19-directed CAR-T cells are administered to the patient after the patient has relapsed or when the patient is treatment resistant.

[0082] In another embodiment, a sequential combination therapy is disclosed that comprises an anti-CD19 antibody and CD19-directed CAR-T cells for use in treating cancer, wherein the anti-CD19 antibody is administered to a cancer patient, and wherein the CD19-directed CAR-T cells are administered to the patient after the patient has relapsed or when the patient is treatment resistant, and wherein the anti-CD19 antibody is administered at least once every two weeks.

[0083] In a further aspect, a sequential combination therapy is disclosed that includes an anti-CD19 antibody and CD19-directed CAR-T cells for use in the treatment of cancer, wherein the anti-CD19 antibody is administered to a cancer patient, and the CD19-directed CAR-T cells are administered to the patient after the patient has a recurrence or when the patient is treatment-resistant, and the anti-CD19 antibody is administered in combination with one or more additional pharmaceutical agents.

[0084] In another aspect, a sequential combination therapy is disclosed that includes an anti-CD19 antibody and CD19-directed CAR-T cells for use in the treatment of cancer, wherein the anti-CD19 antibody is administered to a cancer patient at least once every two weeks, and the CD19-directed CAR-T cells are administered to the patient after the patient has a recurrence or when the patient is treatment-resistant, and the anti-CD19 antibody is administered in combination with one or more additional pharmaceutical agents.

[0085] In one aspect, a sequential combination therapy is disclosed that includes an anti-CD19 antibody and CD19-directed CAR-T cells for use in the treatment of cancer, wherein the anti-CD19 antibody is administered to a cancer patient, and the CD19-directed CAR-T cells are administered to the patient after the patient has a recurrence or when the patient is treatment-resistant, and the anti-CD19 antibody is administered in combination with one or more additional pharmaceutical agents, and the pharmaceutical agent is a biological agent or a chemotherapeutic agent or a pharmaceutically acceptable salt thereof.

[0086] In a further aspect, a sequential combination therapy is disclosed for use in the treatment of cancer, comprising an anti-CD19 antibody and CD19-directed CAR-T cells, wherein the anti-CD19 antibody is administered to a cancer patient and, after the patient experiences a recurrence or if the patient is treatment-resistant, the CD19-directed CAR-T cells are administered to the patient, and wherein the anti-CD19 antibody is administered in combination with one or more additional pharmaceutical agents, which are a therapeutic antibody or antibody fragment, nitrogen mustard, purine analog, thalidomide analog, phosphoinositide 3-kinase inhibitor, BCL-2 inhibitor, Bruton tyrosine kinase (BTK) inhibitor, or a pharmaceutically acceptable salt thereof.

[0087] In a further aspect, a sequential combination therapy is disclosed for use in the treatment of cancer, comprising an anti-CD19 antibody and CD19-directed CAR-T cells, wherein the anti-CD19 antibody is administered to a cancer patient and, after the patient experiences a recurrence or if the patient is treatment-resistant, the CD19-directed CAR-T cells are administered to the patient, and wherein the anti-CD19 antibody is administered in combination with one or more additional pharmaceutical agents, and wherein the pharmaceutical agent is selected from the group consisting of rituximab, R-CHOP, cyclophosphamide, chlorambucil, uracil mustard, ifosfamide, melphalan, bendamustine, mercaptopurine, azathioprine, thioguanine, fludarabine, thalidomide, lenalidomide, pomalidomide, idelalisib, duvelisib, copanlisib, ibrutinib, venetoclax, or a pharmaceutically acceptable salt thereof.

[0088] In a preferred aspect, a sequential combination therapy is disclosed for use in the treatment of cancer, comprising an anti-CD19 antibody and CD19-directed CAR-T cells, wherein the anti-CD19 antibody is administered to a cancer patient and, after the patient experiences a recurrence or if the patient is treatment-resistant, the CD19-directed CAR-T cells are administered to the patient, and wherein the anti-CD19 antibody is administered in combination with one or more additional pharmaceutical agents, which is lenalidomide or a pharmaceutically acceptable salt thereof.

[0089] In certain embodiments, a sequential combination therapy is disclosed that includes an anti-CD19 antibody and CD19-directed CAR-T cells for use in the treatment of cancer. The anti-CD19 antibody is administered to a cancer patient, and in the event of recurrence or if the patient is treatment-resistant, CD19-directed CAR-T cells are administered to the patient. The anti-CD19 antibody is administered in combination with lenalidomide or a pharmaceutically acceptable salt thereof. The anti-CD19 antibody is administered at a dose of at least 12 mg / kg once every two weeks, and lenalidomide is administered daily at a dose of 25 mg.

[0090] In certain embodiments, a sequential combination therapy is disclosed that includes an anti-CD19 antibody and CD19-directed chimeric antigen receptor (CAR) T cells for use in the treatment of cancer. The anti-CD19 antibody is administered to a cancer patient, and in the event of recurrence or if the patient is treatment-resistant, CD19-directed CAR T cells are administered to the patient. The anti-CD19 antibody is administered in combination with lenalidomide or a pharmaceutically acceptable salt thereof. The anti-CD19 antibody is administered at a dose of at least 12 mg / kg once every two weeks, and lenalidomide is administered daily at a dose of 25 mg. The anti-CD19 antibody is administered in a regimen of up to 12 cycles. During cycles 1-3, the anti-CD19 antibody is administered weekly, and after cycle 4, the anti-CD19 antibody is administered every 14 days, and lenalidomide is administered daily.

[0091] In a preferred embodiment, among the sequential treatment combinations disclosed herein for use in the treatment of cancer, the anti-CD19 antibody, which comprises an anti-CD19 antibody and CD19-directed CAR-T cells for use in the treatment of cancer, has an HCDR1 region comprising the sequence SYVMH (SEQ ID NO: 1), an HCDR2 region comprising the sequence NPYNDG (SEQ ID NO: 2), an HCDR3 region comprising the sequence GTYYYGTRVFDY (SEQ ID NO: 3), an LCDR1 region comprising the sequence RSSKSLQNVNGNTYLY (SEQ ID NO: 4), an LCDR2 region comprising the sequence RMSNLNS (SEQ ID NO: 5), and an LCDR3 region comprising the sequence MQHLEYPIT (SEQ ID NO: 6).

[0092] In other embodiments, among the sequential treatment combinations disclosed herein for use in the treatment of cancer, the anti-CD19 antibody, which comprises an anti-CD19 antibody and CD19-directed CAR-T cells for use in the treatment of cancer, has a variable heavy chain of SEQ ID NO: 7 and a variable light chain of SEQ ID NO: 8. In certain embodiments, the sequential treatment combination disclosed herein comprises an anti-CD19 antibody and CD19-directed CAR-T cells for use in the treatment of cancer, and this anti-CD19 antibody has a heavy chain of SEQ ID NO: 11 and a light chain of SEQ ID NO: 12. In some embodiments, the sequential treatment combination disclosed herein comprises tafasitamab and CD19-directed CAR-T cells for use in the treatment of cancer.

[0093] In a preferred embodiment, among the sequential treatment combinations disclosed herein for use in the treatment of cancer, the anti-CD19 antibody, which comprises an anti-CD19 antibody and CD19-directed CAR-T cells for use in the treatment of cancer, has the following i) an HCDR1 region comprising the sequence SYVMH (SEQ ID NO: 1), an HCDR2 region comprising the sequence NPYNDG (SEQ ID NO: 2), an HCDR3 region comprising the sequence GTYYYGTRVFDY (SEQ ID NO: 3), an LCDR1 region comprising the sequence RSSKSLQNVNGNTYLY (SEQ ID NO: 4), an LCDR2 region comprising the sequence RMSNLNS (SEQ ID NO: 5), and an LCDR3 region comprising the sequence MQHLEYPIT (SEQ ID NO: 6), or ii) a variable heavy chain of SEQ ID NO: 7 and a variable light chain of SEQ ID NO: 8, or iii) a heavy chain of SEQ ID NO: 11 and a light chain of SEQ ID NO: 12, or iv) Tafasitamab, and CD19-directed CAR-T cells include axicabtagene ciloleucel (KTE-C19, Axi-cel, YESCARTA®) and / or tisagenlecleucel (CTL019, KYMRIAH®), lisocabtagene maraleucel (JCAR017), or UCART19 (S68587), or a combination of two or more thereof. In another embodiment, the CAR-T cells are one of the CAR-T cell constructs known as KITE037, welgenaleucel, ICTCAR-003, IM-19, CTX-110, SSCAR-010, ICTCAR-011, or a combination of two or more thereof.

[0094] In a preferred embodiment, this cancer, among the sequential treatment combinations disclosed herein, which includes an anti-CD19 antibody and CD19-directed CAR-T cells for use in the treatment of cancer, is a non-Hodgkin B-cell lymphoma, such as follicular lymphoma (FL), small lymphocytic lymphoma (SLL), Burkitt lymphoma, and diffuse large B-cell lymphoma (DLBCL), Waldenström's macroglobulinemia, leukemia, such as chronic lymphocytic leukemia (CLL), acute lymphoblastic leukemia (ALL), or acute myeloid leukemia (AML), etc., and is a hematological cancer selected from. In a preferred embodiment, the hematological cancer is DLBCL. In other embodiments, this cancer is a relapsed or refractory (R / R) cancer, preferably a relapsed or refractory hematological cancer. R / R hematological cancers include R / R non-Hodgkin B-cell lymphomas, such as R / R follicular lymphoma (FL), R / R small lymphocytic lymphoma (SLL), R / R Burkitt lymphoma, and R / R diffuse large B-cell lymphoma (DLBCL), R / R Waldenström's macroglobulinemia, R / R leukemia, such as R / R chronic lymphocytic leukemia (CLL), R / R acute lymphoblastic leukemia (ALL), or R / R acute myeloid leukemia (AML), etc., and are selected from. In a preferred embodiment, the R / R hematological cancer is relapsed or refractory (R / R) diffuse large B-cell lymphoma (DLBCL).

[0095] In one preferred embodiment, the sequential combination therapy comprises tafasitamab and axicabtagene ciloleucel (YESCARTA®) CAR-T cells for use in the treatment of DLBCL in a patient who is treatment-resistant or has relapsed to prior treatment.

[0096] In one preferred embodiment, the sequential combination therapy comprises tafasitamab and axicabtagene ciloleucel (YESCARTA®) CAR-T cells for use in the treatment of DLBCL in a patient who is treatment-resistant or has relapsed to prior treatment, and the prior treatment comprises tafasitamab.

[0097] In another embodiment, an anti-CD19 antibody for use in the treatment of cancer in a patient who has previously been treated with a composition comprising a CD19-directed therapeutic agent is disclosed. In certain embodiments, an anti-CD19 antibody for use in the treatment of cancer in a patient who has previously been treated with a composition comprising CD19-directed CAR-T cells is disclosed.

[0098] In a preferred embodiment, an anti-CD19 antibody having an HCDR1 region comprising the sequence SYVMH (SEQ ID NO: 1), an HCDR2 region comprising the sequence NPYNDG (SEQ ID NO: 2), an HCDR3 region comprising the sequence GTYYYGTRVFDY (SEQ ID NO: 3), an LCDR1 region comprising the sequence RSSKSLQNVNGNTYLY (SEQ ID NO: 4), an LCDR2 region comprising the sequence RMSNLNS (SEQ ID NO: 5), and an LCDR3 region comprising the sequence MQHLEYPIT (SEQ ID NO: 6) for use in the treatment of cancer in a patient who is treatment-resistant or has relapsed to prior treatment, and the prior treatment comprises CD19-directed CAR-T cells is disclosed.

[0099] In another embodiment, an anti-CD19 antibody having a variable heavy chain comprising SEQ ID NO: 7 and / or a variable light chain comprising SEQ ID NO: 8 for use in treating cancer in a patient is disclosed, wherein the patient is treatment resistant or has relapsed to a prior treatment that includes CAR-T cells directed to CD19.

[0100] In one embodiment, an anti-CD19 antibody having a variable heavy chain of SEQ ID NO: 7 and / or a variable light chain of SEQ ID NO: 8 and having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the variable heavy chain and / or variable light chain for use in treating cancer in a patient is disclosed, wherein the patient is treatment resistant or has relapsed to a prior treatment that includes CAR-T cells directed to CD19.

[0101] In certain embodiments, an anti-CD19 antibody having a heavy chain of SEQ ID NO: 11 and a light chain of SEQ ID NO: 12 for use in treating cancer in a patient is disclosed, wherein the patient is treatment resistant or has relapsed to a prior treatment that includes CAR-T cells directed to CD19.

[0102] In certain embodiments, an anti-CD19 antibody comprising tafasitamab for use in treating cancer in a patient is disclosed, wherein the patient is treatment resistant or has relapsed to a prior treatment that includes CAR-T cells directed to CD19.

[0103] In another embodiment, an anti-CD19 antibody for use in treating cancer in a patient is disclosed, wherein the patient is treatment resistant or has relapsed to a prior treatment that includes CAR-T cells directed to CD19, and wherein the chimeric antigen receptor of these CAR-T cells competes with this anti-CD19 antibody for binding to human CD19.

[0104] In other embodiments, anti-CD19 antibodies for use in treating cancer in a patient are disclosed, where the patient is treatment resistant or has relapsed to a prior treatment that included an anti-CD19 therapeutic agent, and the therapeutic agent is selected from the group consisting of an antibody, an antibody-drug conjugate, a bispecific antibody, an alternative scaffold protein, or a CAR-T cell.

[0105] In preferred embodiments, anti-CD19 antibodies for use in treating cancer in a patient are disclosed, where the patient is treatment resistant or has relapsed to a prior treatment that included anti-CD19 CAR-T cells, and the anti-CD19 antibody includes tafasitamab. In certain embodiments, the CAR-T cells are preferably axicabtagene ciloleucel (KTE-C19, Axi-cel, YESCARTA®) and / or tisagenlecleucel (CTL019, KYMRIAH®), lisocabtagene maraleucel (JCAR017, clinical trials: e.g., NCT02631044, NCT03310619), or UCART19, or a combination of two or more thereof. In another embodiment, the CAR-T cells are one of the CAR-T cell constructs known as KITE037, welgenaleucel, ICTCAR-003, IM-19, CTX-110, SSCAR-010, ICTCAR-011, or a combination of two or more thereof.

[0106] In other embodiments, for use in treating cancer in a patient, the antibody is directed to a B cell lineage marker, where the patient is treatment resistant or has relapsed to a prior treatment that included a therapeutic anti-CD19 agent.

[0107] In another embodiment, for use in treating cancer in a patient, the antibody is directed to CD19 and / or CD20, where the patient is treatment resistant or has relapsed to a prior treatment that included a therapeutic anti-CD19 agent.

[0108] In other embodiments, for use in treating cancer in a patient, the antibody is directed against a B cell lineage marker, and the patient is treatment resistant or has relapsed to a prior treatment that included CAR-T cells directed against CD19.

[0109] In another embodiment, for use in treating cancer in a patient, the antibody is directed against CD19 and / or CD20, and the patient is treatment resistant or has relapsed to a prior treatment that included CAR-T cells directed against CD19.

[0110] In a preferred embodiment, the antibody directed against a B cell lineage marker (e.g., CD19 and / or CD20) is for use in a pharmaceutical composition. In other embodiments, the antibody directed against a B cell lineage marker (e.g., CD19 and / or CD20) is included in a pharmaceutical composition.

[0111] In one embodiment, an anti-CD19 antibody for use in treating cancer in a patient is disclosed, where the patient has been previously treated with a composition comprising CD19-directed CAR-T cells, and the cancer is a blood cancer. In certain embodiments, the blood cancer is selected from non-Hodgkin B cell lymphoma, such as follicular lymphoma (FL), small lymphocytic lymphoma (SLL), Burkitt lymphoma, and diffuse large B cell lymphoma (DLBCL), Waldenström macroglobulinemia, leukemia, such as chronic lymphocytic leukemia (CLL), acute lymphoblastic leukemia (ALL), or acute myeloid leukemia (AML). In a preferred embodiment, the blood cancer is DLBCL. In other embodiments, the cancer is a relapsed or refractory (R / R) cancer, preferably a relapsed or refractory blood cancer. R / R blood cancers are selected from R / R non-Hodgkin B cell lymphoma, such as R / R follicular lymphoma (FL), R / R small lymphocytic lymphoma (SLL), R / R Burkitt lymphoma, and R / R diffuse large B cell lymphoma (DLBCL), R / R Waldenström macroglobulinemia, R / R leukemia, such as R / R chronic lymphocytic leukemia (CLL), R / R acute lymphoblastic leukemia (ALL), or R / R acute myeloid leukemia (AML). In a preferred embodiment, the R / R blood cancer is relapsed or refractory (R / R) diffuse large B cell lymphoma (DLBCL).

[0112] In certain embodiments, an anti-CD19 antibody for use in treating R / R DLBCL in a patient is disclosed, where the patient is treatment resistant or has relapsed to prior treatment, the prior treatment comprising CD19-directed CAR-T cells, and the anti-CD19 antibody has the following i) an HCDR1 region comprising the sequence SYVMH (SEQ ID NO: 1), an HCDR2 region comprising the sequence NPYNDG (SEQ ID NO: 2), an HCDR3 region comprising the sequence GTYYYGTRVFDY (SEQ ID NO: 3), an LCDR1 region comprising the sequence RSSKSLQNVNGNTYLY (SEQ ID NO: 4), an LCDR2 region comprising the sequence RMSNLNS (SEQ ID NO: 5), and an LCDR3 region comprising the sequence MQHLEYPIT (SEQ ID NO: 6), or ii) The variable heavy chain of SEQ ID NO: 7 and the variable light chain of SEQ ID NO: 8, or iii) The heavy chain of SEQ ID NO: 11 and the light chain of SEQ ID NO: 12, or iv) Ofatumumab.

[0113] In certain embodiments, the combination of ofatumumab and lenalidomide for use in treating R / R DLBCL in a patient is disclosed, where the patient is treatment resistant or has relapsed to a prior treatment that includes CD19-directed CAR-T cells.

[0114] In another embodiment, the combination of ofatumumab and bendamustine for use in treating R / R DLBCL in a patient is disclosed, where the patient is treatment resistant or has relapsed to a prior treatment that includes CD19-directed CAR-T cells.

[0115] Treatment methods In one embodiment, a method of treating cancer in a patient with CD19-directed CAR-T cells is disclosed, where the patient is treatment resistant or has relapsed to a prior treatment that includes an anti-CD19 antibody.

[0116] In one embodiment, a method of treating cancer in a patient with a pharmaceutical composition comprising CD19-directed CAR-T cells is disclosed, where the patient is treatment resistant or has relapsed to a prior treatment that includes an anti-CD19 antibody.

[0117] In one embodiment, a method of treating cancer in a patient with a pharmaceutical composition comprising CD19-directed CAR-T cells in a second, third, fourth, or any other multiple subsequent treatment regimen is disclosed, where the patient is treatment resistant or has relapsed to a prior treatment regimen that includes an anti-CD19 antibody.

[0118] In another embodiment, a method of treating cancer in a patient with a pharmaceutical composition comprising CD19-directed CAR-T cells in a second, third, fourth, or any other plurality of subsequent treatment regimens is disclosed, wherein the patient has been administered a pharmaceutical composition comprising an anti-CD19 antibody in at least one of the prior treatment regimen(s).

[0119] In another embodiment, a method of treating cancer in a patient with a pharmaceutical composition comprising CD19-directed CAR-T cells in a second, third, fourth, or any other plurality of subsequent treatment regimens is disclosed, wherein the patient has been administered a pharmaceutical composition comprising an anti-CD19 antibody in at least one of the prior treatment regimen(s), and wherein the patient is treatment-resistant or has relapsed after at least one of the prior treatment regimen(s).

[0120] In another embodiment, a method of treating hematological cancer in a patient with a pharmaceutical composition comprising CD19-directed CAR-T cells in a second, third, fourth, or any other plurality of subsequent treatment regimens is disclosed, wherein the patient has been administered a pharmaceutical composition comprising tafasitamab in at least one of the prior treatment regimen(s).

[0121] In one embodiment, a method of treating cancer in a patient in a second, third, fourth, or any other plurality of subsequent treatment regimens is disclosed, the method comprising the following steps i) identifying a patient who has been administered a pharmaceutical composition comprising an anti-CD19 antibody, the antibody having an HCDR1 region comprising the sequence SYVMH (SEQ ID NO: 1), an HCDR2 region comprising the sequence NPYNDG (SEQ ID NO: 2), an HCDR3 region comprising the sequence GTYYYGTRVFDY (SEQ ID NO: 3), an LCDR1 region comprising the sequence RSSKSLQNVNGNTYLY (SEQ ID NO: 4), an LCDR2 region comprising the sequence RMSNLNS (SEQ ID NO: 5), and an LCDR3 region comprising the sequence MQHLEYPIT (SEQ ID NO: 6), and ii) administering to the patient, in the second, third, fourth, or any other plurality of subsequent treatment regimens, a further pharmaceutical composition comprising a CD19-directed therapeutic agent.

[0122] In one embodiment, a method of treating cancer in a patient in a second, third, fourth, or any other plurality of subsequent treatment regimens is disclosed, the method comprising the following steps i) identifying a patient who has been administered a pharmaceutical composition comprising an anti-CD19 antibody, the antibody having a variable heavy chain of SEQ ID NO: 7 and / or a variable light chain of SEQ ID NO: 8, and ii) administering to the patient, in the second, third, fourth, or any other plurality of subsequent treatment regimens, a further pharmaceutical composition comprising a CD19-directed therapeutic agent.

[0123] In one embodiment, a method of treating cancer in a patient in a second, third, fourth, or any other plurality of subsequent treatment regimens is disclosed, the method comprising the following steps i) identifying a patient who has been administered a pharmaceutical composition comprising an anti-CD19 antibody, the antibody having a heavy chain of SEQ ID NO: 11 and / or a light chain of SEQ ID NO: 12, and ii) administering to the patient, in the second, third, fourth, or any other plurality of subsequent treatment regimens, a further pharmaceutical composition comprising a CD19-directed therapeutic agent.

[0124] In one embodiment, a method of treating cancer in a patient in a second, third, fourth, or any other plurality of subsequent treatment regimens is disclosed, the method comprising the following steps i) identifying a patient who has been administered a pharmaceutical composition comprising the anti-CD19 antibody tafasitamab, and ii) administering to the patient, in the second, third, fourth, or any other plurality of subsequent treatment regimens, a further pharmaceutical composition comprising a CD19-directed therapeutic agent.

[0125] In certain embodiments, the CD19-directed therapeutic agent in the second, third, fourth, or any other plurality of treatment regimens in step (ii) is a monoclonal antibody, an antibody-drug conjugate, a bispecific antibody, an alternative scaffold protein, or a chimeric antigen receptor (CAR) T cell. Preferably, the CD19-directed therapeutic agent in the pharmaceutical composition of the second, third, fourth, or any other plurality of treatment regimens is a CAR-T cell.

[0126] In one embodiment, a method of treating cancer in a patient with a second, third, fourth, or any other plurality of treatment regimens is disclosed, the method comprising the following steps i) identifying a patient who has been administered a pharmaceutical composition comprising the anti-CD19 antibody tafasitamab, and ii) administering to the patient, in the second, third, fourth, or any other plurality of treatment regimens, a further pharmaceutical composition comprising CAR-T cells directed to CD19.

[0127] In one embodiment, a method of treating cancer in a patient with a second, third, fourth, or any other plurality of treatment regimens is disclosed, the method comprising the following steps i) identifying a patient who has been administered a pharmaceutical composition comprising the anti-CD19 antibody tafasitamab, and ii) administering to the patient, in the second, third, fourth, or any other plurality of treatment regimens, a further pharmaceutical composition comprising CAR-T cells directed to CD19, the CAR-T cells being selected from one or more of axicabtagene ciloleucel, tisagenlecleucel, lisocabtagene maraleucel, and / or UCART19, or combinations thereof.

[0128] In one embodiment, a method of treating R / R DLBCL in a patient with a second, third, fourth, or any other plurality of treatment regimens is disclosed, the method comprising the following steps i) Identifying a patient who has been administered a pharmaceutical composition comprising the anti-CD19 antibody tafasitamab, and ii) Administering to the patient, in the second, third, fourth, or any other plurality of subsequent treatment regimens, a further pharmaceutical composition comprising CD19-directed CAR-T cells, which CAR-T cells are selected from one of axicabtagene ciloleucel, tisagenlecleucel, lisocabtagene maraleucel, and / or UCART19, or a combination thereof.

[0129] In some embodiments, a method of treating relapsed or refractory CD19+ hematologic cancer using a therapeutic anti-CD19 agent is disclosed, the method comprising the following steps a) Identifying a patient with relapsed or refractory CD19+ hematologic cancer, and b) Administering to the patient an effective amount of a CD19-directed therapeutic agent, wherein the patient has been treated with a pharmaceutical composition comprising an anti-CD19 antibody prior to step a), and the antibody has i) an HCDR1 region comprising the sequence SYVMH (SEQ ID NO: 1), an HCDR2 region comprising the sequence NPYNDG (SEQ ID NO: 2), an HCDR3 region comprising the sequence GTYYYGTRVFDY (SEQ ID NO: 3), an LCDR1 region comprising the sequence RSSKSLQNVNGNTYLY (SEQ ID NO: 4), an LCDR2 region comprising the sequence RMSNLNS (SEQ ID NO: 5), and an LCDR3 region comprising the sequence MQHLEYPIT (SEQ ID NO: 6), or ii) a variable heavy chain of SEQ ID NO: 7 and a variable light chain of SEQ ID NO: 8, or iii) a heavy chain of SEQ ID NO: 11 and a light chain of SEQ ID NO: 12, or iv) tafasitamab.

[0130] In certain embodiments, a method of treating relapsed or refractory CD19+ hematologic cancer using CD19-directed CAR-T cells is disclosed, the method comprising the following steps a) Identifying a patient with relapsed or refractory CD19+ hematologic cancer, and b) Administering to the patient an effective amount of CD19-directed CAR-T cells, wherein the patient has been treated with a pharmaceutical composition comprising an anti-CD19 antibody prior to step a), and the antibody has i) an HCDR1 region comprising the sequence SYVMH (SEQ ID NO: 1), an HCDR2 region comprising the sequence NPYNDG (SEQ ID NO: 2), an HCDR3 region comprising the sequence GTYYYGTRVFDY (SEQ ID NO: 3), an LCDR1 region comprising the sequence RSSKSLQNVNGNTYLY (SEQ ID NO: 4), an LCDR2 region comprising the sequence RMSNLNS (SEQ ID NO: 5), and an LCDR3 region comprising the sequence MQHLEYPIT (SEQ ID NO: 6), or ii) a variable heavy chain of SEQ ID NO: 7 and a variable light chain of SEQ ID NO: 8, or iii) a heavy chain of SEQ ID NO: 11 and a light chain of SEQ ID NO: 12, or iv) tofacitinib.

[0131] In certain embodiments, a method of treating relapsed or refractory DLBCL using CD19-directed CAR-T cells is disclosed, the method comprising the following steps a) Identifying a patient with relapsed or refractory DLBCL, and b) Administering to the patient an effective amount of CD19-directed CAR-T cells, wherein the patient has been treated with a pharmaceutical composition comprising an anti-CD19 antibody prior to step a), and the antibody has i) an HCDR1 region comprising the sequence SYVMH (SEQ ID NO: 1), an HCDR2 region comprising the sequence NPYNDG (SEQ ID NO: 2), an HCDR3 region comprising the sequence GTYYYGTRVFDY (SEQ ID NO: 3), an LCDR1 region comprising the sequence RSSKSLQNVNGNTYLY (SEQ ID NO: 4), an LCDR2 region comprising the sequence RMSNLNS (SEQ ID NO: 5), and an LCDR3 region comprising the sequence MQHLEYPIT (SEQ ID NO: 6), or ii) a variable heavy chain of SEQ ID NO: 7 and a variable light chain of SEQ ID NO: 8, or iii) a heavy chain of SEQ ID NO: 11 and a light chain of SEQ ID NO: 12, or iv) tofacitinib.

[0132] In one aspect, provided is a treatment method involving: (1) administering to a patient having cancer a composition comprising an anti-CD19 antibody, which antibody has i) an HCDR1 region comprising the sequence SYVMH (SEQ ID NO: 1), an HCDR2 region comprising the sequence NPYNDG (SEQ ID NO: 2), an HCDR3 region comprising the sequence GTYYYGTRVFDY (SEQ ID NO: 3), an LCDR1 region comprising the sequence RSSKSLQNVNGNTYLY (SEQ ID NO: 4), an LCDR2 region comprising the sequence RMSNLNS (SEQ ID NO: 5), and an LCDR3 region comprising the sequence MQHLEYPIT (SEQ ID NO: 6), or ii) a variable heavy chain of SEQ ID NO: 7 and a variable light chain of SEQ ID NO: 8, or iii) a heavy chain of SEQ ID NO: 11 and a light chain of SEQ ID NO: 12, or iv) tafasitamab, and (2) when the patient is relapsed or refractory, sequentially administering to the patient a composition comprising T cells that express a recombinant receptor that is autologous to the patient and specifically binds to CD19.

[0133] In a preferred embodiment, the CD19-directed autologous T cells for use in treating cancer in a patient are chimeric antigen receptor (CAR) T cells when the patient has been previously treated with a composition comprising an anti-CD19 antibody. In certain embodiments, the CAR-T cells are preferably axicabtagene ciloleucel (KTE-C19, Axi-cel, Yescarta®) and / or tisagenlecleucel (CTL019, Kymriah®), lisocabtagene maraleucel (JCAR017, clinical trials: e.g., NCT02631044, NCT03310619), or UCART19, or a combination of two or more thereof. In another embodiment, the CAR-T cells are one of the CAR-T cell constructs known as KITE037, welgenaleucel, ICTCAR-003, IM-19, CTX-110, SSCAR-010, ICTCAR-011, or a combination of two or more thereof.

[0134] In one embodiment, a method of treating cancer in a patient with an anti-CD19 antibody is disclosed, where the patient is treatment resistant or has experienced recurrence to a prior treatment that includes CAR-T cells directed to CD19.

[0135] In one embodiment, a method of treating cancer in a patient with a composition comprising an anti-CD19 antibody is disclosed, where the patient is treatment resistant or has experienced recurrence to a prior treatment that includes CAR-T cells directed to CD19.

[0136] In one embodiment, a method of treating cancer in a patient with a pharmaceutical composition comprising an anti-CD19 antibody in a second, third, fourth, or any other multiple subsequent treatment regimen is disclosed, where the patient is treatment resistant or has experienced recurrence and has been administered a pharmaceutical composition comprising CAR-T cells directed to CD19 in a prior treatment regimen.

[0137] In another embodiment, a method of treating cancer in a patient with a pharmaceutical composition comprising an anti-CD19 antibody in a second, third, fourth, or any other multiple subsequent treatment regimen is disclosed, where the patient is treatment resistant or has experienced recurrence and has been administered a pharmaceutical composition comprising CAR-T cells directed to CD19 in one of the prior treatment regimens (s).

[0138] In one embodiment, a method of treating cancer in a patient in a second, third, fourth, or any other multiple subsequent treatment regimen is disclosed, the method comprising the following steps i) identifying a patient who has been administered a pharmaceutical composition comprising CAR-T cells directed to CD19, and ii) administering to the patient a further pharmaceutical composition comprising an anti-CD19 antibody in the second, third, fourth, or any other plurality of subsequent treatment regimens, said antibody having an HCDR1 region comprising the sequence SYVMH (SEQ ID NO: 1), an HCDR2 region comprising the sequence NPYNDG (SEQ ID NO: 2), an HCDR3 region comprising the sequence GTYYYGTRVFDY (SEQ ID NO: 3), an LCDR1 region comprising the sequence RSSKSLQNVNGNTYLY (SEQ ID NO: 4), an LCDR2 region comprising the sequence RMSNLNS (SEQ ID NO: 5), and an LCDR3 region comprising the sequence MQHLEYPIT (SEQ ID NO: 6).

[0139] In one embodiment, a method of treating cancer in a patient in a second, third, fourth, or any other plurality of subsequent treatment regimens is disclosed, the method comprising the following steps i) identifying a patient who has been administered a pharmaceutical composition comprising CD19-directed CAR-T cells, and ii) administering to the patient a further pharmaceutical composition comprising an anti-CD19 antibody in the second, third, fourth, or any other plurality of subsequent treatment regimens, said antibody having a variable heavy chain of SEQ ID NO: 7 and / or a variable light chain of SEQ ID NO: 8.

[0140] In one embodiment, a method of treating cancer in a patient in a second, third, fourth, or any other plurality of subsequent treatment regimens is disclosed, the method comprising the following steps i) identifying a patient who has been administered a pharmaceutical composition comprising CD19-directed CAR-T cells, and ii) administering to the patient a further pharmaceutical composition comprising an anti-CD19 antibody in the second, third, fourth, or any other plurality of subsequent treatment regimens, said antibody having a heavy chain of SEQ ID NO: 11 and / or a light chain of SEQ ID NO: 12.

[0141] In one embodiment, a method of treating cancer in a patient in a second, third, fourth, or any other plurality of subsequent treatment regimens is disclosed, the method comprising the following steps i) Identifying a patient who has been administered a pharmaceutical composition comprising CD19-directed CAR-T cells, and ii) Administering to the patient, in the second, third, fourth, or any other subsequent treatment regimen, a further pharmaceutical composition comprising the anti-CD19 antibody tafasitamab.

[0142] In one embodiment, a method of treating cancer in a patient in a second, third, fourth, or any other subsequent treatment regimen is disclosed, the method comprising the following steps i) Identifying a patient who has been administered a pharmaceutical composition comprising CD19-directed CAR-T cells, the CAR-T cells being selected from one or more of axicabtagene ciloleucel, tisagenlecleucel, lisocabtagene maraleucel, and / or UCART19, or combinations thereof, and ii) Administering to the patient, in the second, third, fourth, or any other subsequent treatment regimen, a further pharmaceutical composition comprising the anti-CD19 antibody tafasitamab.

[0143] In one embodiment, a method of treating R / R DLBCL in a patient in a second, third, fourth, or any other subsequent treatment regimen is disclosed, the method comprising the following steps i) Identifying a patient who has been administered a pharmaceutical composition comprising CD19-directed CAR-T cells, the CAR-T cells being selected from one or more of axicabtagene ciloleucel, tisagenlecleucel, lisocabtagene maraleucel, and / or UCART19, or combinations thereof, and ii) Administering to the patient, in the second, third, fourth, or any other subsequent treatment regimen, a further pharmaceutical composition comprising the anti-CD19 antibody tafasitamab.

[0144] In some embodiments, a method of treating relapsed or refractory CD19+ hematologic cancer using an anti-CD19 antibody is disclosed, the method comprising the following steps a) Identifying a patient with relapsed or refractory CD19+ blood cancer, and b) Administering to the patient an effective amount of an anti-CD29 antibody, where the patient has been previously treated with a pharmaceutical composition comprising CAR-T cells directed to CD19, and the anti-CD19 antibody of step (b) has i) an HCDR1 region comprising the sequence SYVMH (SEQ ID NO: 1), an HCDR2 region comprising the sequence NPYNDG (SEQ ID NO: 2), an HCDR3 region comprising the sequence GTYYYGTRVFDY (SEQ ID NO: 3), an LCDR1 region comprising the sequence RSSKSLQNVNGNTYLY (SEQ ID NO: 4), an LCDR2 region comprising the sequence RMSNLNS (SEQ ID NO: 5), and an LCDR3 region comprising the sequence MQHLEYPIT (SEQ ID NO: 6), or ii) a variable heavy chain of SEQ ID NO: 7 and a variable light chain of SEQ ID NO: 8, or iii) a heavy chain of SEQ ID NO: 11 and a light chain of SEQ ID NO: 12, or iv) tofacitinib.

[0145] Provided in some embodiments is a treatment method involving: (1) administering to a patient having cancer a composition comprising T cells expressing a recombinant receptor that is autologous to the patient and specifically binds to CD19 associated with the cancer, and (2) sequentially administering to the patient a composition comprising an anti-CD19 antibody when the patient is treatment-resistant or has relapsed, the antibody comprising i) an HCDR1 region comprising the sequence SYVMH (SEQ ID NO: 1), an HCDR2 region comprising the sequence NPYNDG (SEQ ID NO: 2), an HCDR3 region comprising the sequence GTYYYGTRVFDY (SEQ ID NO: 3), an LCDR1 region comprising the sequence RSSKSLQNVNGNTYLY (SEQ ID NO: 4), an LCDR2 region comprising the sequence RMSNLNS (SEQ ID NO: 5), and an LCDR3 region comprising the sequence MQHLEYPIT (SEQ ID NO: 6), or ii) a variable heavy chain of SEQ ID NO: 7 and a variable light chain of SEQ ID NO: 8, or iii) a heavy chain of SEQ ID NO: 11 and a light chain of SEQ ID NO: 12, or iv) tofacitinib.

[0146] In a preferred embodiment, autologous T cells directed to CD19 for use in treating cancer in a patient are chimeric antigen receptor (CAR) T cells when the patient is treatment resistant or has relapsed and when the patient is sequentially treated with a composition comprising an anti-CD19 antibody. In certain embodiments, the CAR-T cells are preferably axicabtagene ciloleucel (KTE-C19, Axi-cel, YESCARTA®) and / or tisagenlecleucel (CTL019, KYMRIAH®), lisocabtagene maraleucel (JCAR017, clinical trials: e.g., NCT02631044, NCT03310619), or UCART19, or a combination of two or more thereof. In another embodiment, the CAR-T cells are one of the (CAR) T cell constructs known as KITE037, welgenaleucel, ICTCAR-003, IM-19, CTX-110, SSCAR-010, ICTCAR-011, or a combination of two or more thereof.

[0147] Method for predicting response In another embodiment, a method is disclosed for determining whether a patient is likely to respond or is likely to not respond to CD19-directed CAR-T cell therapy following treatment with tafasitamab, the method comprising the following steps a) contacting a tumor sample isolated from the patient with an anti-CD19 antibody having an effective amount of a variable heavy chain of SEQ ID NO: 7 and a variable light chain of SEQ ID NO: 8 to saturate the antigen in vitro; b) adding CAR-T cells directed to CD19 at various effector:target ratios; and c) evaluating CAR-T cell effector function (e.g., antigen-specific killing, degranulation, cytokine production, or proliferation). In this case, the presence of CAR-T cell effector function indicates that this patient is likely to respond to anti-CD19 CAR-T cell therapy, and the absence of CAR-T cell effector function indicates that this patient is less likely to respond to anti-CD19 CAR-T cell therapy.

[0148] In another embodiment, a method is disclosed for determining whether a patient who is treatment-resistant or has relapsed is likely to respond or is less likely to respond to CD19-directed CAR-T cell therapy following treatment with tafasitamab, the method comprising the following steps a) contacting a tumor sample isolated from a patient with an effective amount of an anti-CD19 antibody having a variable heavy chain of SEQ ID NO: 7 and a variable light chain of SEQ ID NO: 8 to saturate the antigen in vitro; b) adding CAR-T cells directed against CD19 at various effector:target ratios; and c) evaluating CAR-T cell effector function (e.g., antigen-specific killing, degranulation, cytokine production, or proliferation); In this case, the presence of CAR-T cell effector function indicates that this patient is likely to respond to anti-CD19 CAR-T cell therapy, and the absence of CAR-T cell effector function indicates that this patient is less likely to respond to anti-CD19 CAR-T cell therapy.

[0149] In certain embodiments, the various effector:target (E:T) ratios are 0:1, 0.3125:1, 0.625:1, 1.25:1, 2.5:1, 5:1, and 10:1. In one embodiment, the anti-CD19 CAR-T cells comprise a CAR construct of the format FMC63-CD8h-CD8TM-41BBζ.

[0150] Use of a CD19-directed therapeutic agent in the manufacture of a medicament for treating a blood cancer in a patient who is treatment-resistant or has relapsed to a prior treatment comprising an anti-CD19 antibody, the antibody having the following i) An HCDR1 region containing the sequence SYVMH (SEQ ID NO: 1), an HCDR2 region containing the sequence NPYNDG (SEQ ID NO: 2), an HCDR3 region containing the sequence GTYYYGTRVFDY (SEQ ID NO: 3), an LCDR1 region containing the sequence RSSKSLQNVNGNTYLY (SEQ ID NO: 4), an LCDR2 region containing the sequence RMSNLNS (SEQ ID NO: 5), and an LCDR3 region containing the sequence MQHLEYPIT (SEQ ID NO: 6), or ii) A variable heavy chain of SEQ ID NO: 7 and a variable light chain of SEQ ID NO: 8, or iii) A heavy chain of SEQ ID NO: 11 and a light chain of SEQ ID NO: 12, or iv) Ofatumumab.

[0151] Use of CD19-directed CAR-T cells in the manufacture of a medicament for treating blood cancer in a patient who is treatment-resistant or has relapsed to a prior treatment that includes an anti-CD19 antibody having i) An HCDR1 region containing the sequence SYVMH (SEQ ID NO: 1), an HCDR2 region containing the sequence NPYNDG (SEQ ID NO: 2), an HCDR3 region containing the sequence GTYYYGTRVFDY (SEQ ID NO: 3), an LCDR1 region containing the sequence RSSKSLQNVNGNTYLY (SEQ ID NO: 4), an LCDR2 region containing the sequence RMSNLNS (SEQ ID NO: 5), and an LCDR3 region containing the sequence MQHLEYPIT (SEQ ID NO: 6), or ii) A variable heavy chain of SEQ ID NO: 7 and a variable light chain of SEQ ID NO: 8, or iii) A heavy chain of SEQ ID NO: 11 and a light chain of SEQ ID NO: 12, or iv) Ofatumumab.

[0152] Use of CD19-directed CAR-T cells in the manufacture of a medicament for treating blood cancer in a patient who is treatment-resistant or has relapsed to a prior treatment that includes an anti-CD19 antibody having i) An HCDR1 region containing the sequence SYVMH (SEQ ID NO: 1), an HCDR2 region containing the sequence NPYNDG (SEQ ID NO: 2), an HCDR3 region containing the sequence GTYYYGTRVFDY (SEQ ID NO: 3), an LCDR1 region containing the sequence RSSKSLQNVNGNTYLY (SEQ ID NO: 4), an LCDR2 region containing the sequence RMSNLNS (SEQ ID NO: 5), and an LCDR3 region containing the sequence MQHLEYPIT (SEQ ID NO: 6), or ii) A variable heavy chain of SEQ ID NO: 7 and a variable light chain of SEQ ID NO: 8, or iii) A heavy chain of SEQ ID NO: 11 and a light chain of SEQ ID NO: 12, or iv) Tafasitamab, and the CD19-directed CAR-T cells are selected from the group consisting of axicabtagene ciloleucel (YESCARTA®), tisagenlecleucel (KYMRIAH®), lisocabtagene maraleucel, or UCART19.

[0153] Use of CD19-directed CAR-T cells in the manufacture of a medicament for treating blood cancer in a patient, wherein the patient is treatment-resistant or has relapsed to a previous treatment, the previous treatment comprising an anti-CD19 antibody, the antibody having i) An HCDR1 region containing the sequence SYVMH (SEQ ID NO: 1), an HCDR2 region containing the sequence NPYNDG (SEQ ID NO: 2), an HCDR3 region containing the sequence GTYYYGTRVFDY (SEQ ID NO: 3), an LCDR1 region containing the sequence RSSKSLQNVNGNTYLY (SEQ ID NO: 4), an LCDR2 region containing the sequence RMSNLNS (SEQ ID NO: 5), and an LCDR3 region containing the sequence MQHLEYPIT (SEQ ID NO: 6), or ii) A variable heavy chain of SEQ ID NO: 7 and a variable light chain of SEQ ID NO: 8, or iii) A heavy chain of SEQ ID NO: 11 and a light chain of SEQ ID NO: 12, or iv) Tafasitamab, and this blood cancer is selected from non-Hodgkin B-cell lymphoma, such as follicular lymphoma (FL), small lymphocytic lymphoma (SLL), Burkitt lymphoma, and diffuse large B-cell lymphoma (DLBCL), Waldenström macroglobulinemia, leukemia, such as chronic lymphocytic leukemia (CLL), acute lymphoblastic leukemia (ALL), or acute myeloid leukemia (AML), relapsed or refractory (R / R) non-Hodgkin B-cell lymphoma, such as R / R follicular lymphoma (FL), R / R small lymphocytic lymphoma (SLL), R / R Burkitt lymphoma, and R / R diffuse large B-cell lymphoma (DLBCL), R / R Waldenström macroglobulinemia, R / R leukemia, such as R / R chronic lymphocytic leukemia (CLL), R / R acute lymphoblastic leukemia (ALL), or R / R acute myeloid leukemia (AML), preferably R / R DLBCL.

[0154] Use of axicabtagene ciloleucel (YESCARTA®) CAR-T cells directed to CD19 in the manufacture of a medicament for treating R / R DLBCL in a patient who is treatment-resistant or has relapsed to prior treatment, which prior treatment includes the anti-CD19 antibody tafasitamab.

[0155] Use of an anti-CD19 antibody in the manufacture of a medicament for treating blood cancer in a patient who is treatment-resistant or has relapsed to prior treatment, which prior treatment includes CAR-T cells directed to CD19, and which anti-CD19 antibody has i) an HCDR1 region comprising the sequence SYVMH (SEQ ID NO: 1), an HCDR2 region comprising the sequence NPYNDG (SEQ ID NO: 2), an HCDR3 region comprising the sequence GTYYYGTRVFDY (SEQ ID NO: 3), an LCDR1 region comprising the sequence RSSKSLQNVNGNTYLY (SEQ ID NO: 4), an LCDR2 region comprising the sequence RMSNLNS (SEQ ID NO: 5), and an LCDR3 region comprising the sequence MQHLEYPIT (SEQ ID NO: 6), or ii) a variable heavy chain of SEQ ID NO: 7 and a variable light chain of SEQ ID NO: 8, or iii) The heavy chain of SEQ ID NO: 11 and the light chain of SEQ ID NO: 12, or iv) Tafasitamab.

[0156] Use of an anti-CD19 antibody in the manufacture of a medicament for treating blood cancer in a patient who is treatment-resistant or has relapsed to a previous treatment that includes CD19-directed CAR-T cells, and wherein the anti-CD19 antibody has i) An HCDR1 region comprising the sequence SYVMH (SEQ ID NO: 1), an HCDR2 region comprising the sequence NPYNDG (SEQ ID NO: 2), an HCDR3 region comprising the sequence GTYYYGTRVFDY (SEQ ID NO: 3), an LCDR1 region comprising the sequence RSSKSLQNVNGNTYLY (SEQ ID NO: 4), an LCDR2 region comprising the sequence RMSNLNS (SEQ ID NO: 5), and an LCDR3 region comprising the sequence MQHLEYPIT (SEQ ID NO: 6), or ii) A variable heavy chain of SEQ ID NO: 7 and a variable light chain of SEQ ID NO: 8, or iii) The heavy chain of SEQ ID NO: 11 and the light chain of SEQ ID NO: 12, or iv) Tafasitamab, and the CD19-directed CAR-T cell is selected from the group consisting of axicabtagene ciloleucel (YESCARTA®), tisagenlecleucel (KYMRIAH®), lisocabtagene maraleucel, or UCART19.

[0157] Use of an anti-CD19 antibody in the manufacture of a medicament for treating blood cancer in a patient who is treatment-resistant or has relapsed to a previous treatment that includes CD19-directed CAR-T cells, and wherein the antibody has i) An HCDR1 region comprising the sequence SYVMH (SEQ ID NO: 1), an HCDR2 region comprising the sequence NPYNDG (SEQ ID NO: 2), an HCDR3 region comprising the sequence GTYYYGTRVFDY (SEQ ID NO: 3), an LCDR1 region comprising the sequence RSSKSLQNVNGNTYLY (SEQ ID NO: 4), an LCDR2 region comprising the sequence RMSNLNS (SEQ ID NO: 5), and an LCDR3 region comprising the sequence MQHLEYPIT (SEQ ID NO: 6), or ii) the variable heavy chain of SEQ ID NO: 7 and the variable light chain of SEQ ID NO: 8, or iii) the heavy chain of SEQ ID NO: 11 and the light chain of SEQ ID NO: 12, or iv) ofatumumab, and this blood cancer is selected from non-Hodgkin B-cell lymphoma, such as follicular lymphoma (FL), small lymphocytic lymphoma (SLL), Burkitt lymphoma, and diffuse large B-cell lymphoma (DLBCL), Waldenström macroglobulinemia, leukemia, such as chronic lymphocytic leukemia (CLL), acute lymphoblastic leukemia (ALL), or acute myeloid leukemia (AML), etc., relapsed or refractory (R / R) non-Hodgkin B-cell lymphoma, such as R / R follicular lymphoma (FL), R / R small lymphocytic lymphoma (SLL), R / R Burkitt lymphoma, and R / R diffuse large B-cell lymphoma (DLBCL), etc., R / R Waldenström macroglobulinemia, R / R leukemia, such as R / R chronic lymphocytic leukemia (CLL), R / R acute lymphoblastic leukemia (ALL), or R / R acute myeloid leukemia (AML), etc., preferably R / R DLBCL.

[0158] Use of an anti-CD19 antibody in the manufacture of a medicament for treating R / R DLBCL in a patient who is treatment-resistant or has relapsed to prior treatment, which prior treatment includes CAR-T cells directed against CD19, and this antibody has i) an HCDR1 region containing the sequence SYVMH (SEQ ID NO: 1), an HCDR2 region containing the sequence NPYNDG (SEQ ID NO: 2), an HCDR3 region containing the sequence GTYYYGTRVFDY (SEQ ID NO: 3), an LCDR1 region containing the sequence RSSKSLQNVNGNTYLY (SEQ ID NO: 4), an LCDR2 region containing the sequence RMSNLNS (SEQ ID NO: 5), and an LCDR3 region containing the sequence MQHLEYPIT (SEQ ID NO: 6), or ii) the variable heavy chain of SEQ ID NO: 7 and the variable light chain of SEQ ID NO: 8, or iii) the heavy chain of SEQ ID NO: 11 and the light chain of SEQ ID NO: 12, or iv) ofatumumab.

[0159] Use of tafasitamab in the manufacture of a medicament for treating R / R DLBCL in a patient who is treatment resistant or has relapsed to prior treatment, which prior treatment includes CD19-directed CAR-T cells.

Claims

1. A therapeutic agent for treating blood cancer in a patient, comprising chimeric antigen receptor (CAR) T cells directed against CD19, wherein the patient is treatment-resistant to prior treatment or has relapsed, and the prior treatment comprises an anti-CD19 antibody having an HCDR1 region comprising the sequence SYVMH (SEQ ID NO: 1), an HCDR2 region comprising the sequence NPYNDG (SEQ ID NO: 2), an HCDR3 region comprising the sequence GTYYYYGTRVF DY (SEQ ID NO: 3), an LCDR1 region comprising the sequence RSSKS LQNVNGNTYLY (SEQ ID NO: 4), an LCDR2 region comprising the sequence RMSNLNS (SEQ ID NO: 5), and an LCDR3 region comprising the sequence MQHLEYPIT (SEQ ID NO: 6), said therapeutic agent.

2. The therapeutic agent according to claim 1, wherein the anti-CD19 antibody has a variable heavy chain of SEQ ID NO: 7 and a variable light chain of SEQ ID NO:

8.

3. The therapeutic agent according to claim 1, wherein the anti-CD19 antibody has a variable heavy chain of SEQ ID NO: 11 and a variable light chain of SEQ ID NO:

12.

4. The therapeutic agent according to any one of claims 1 to 3, wherein the CAR-T cells are axicabtagene ciloleucel, tisagenlecleucel, lisocabtagene maraleucel, or UCART19.

5. The therapeutic agent according to any one of claims 1 to 4, wherein the blood cancer is non-Hodgkin B cell lymphoma.

6. The therapeutic agent according to claim 5, wherein the non-Hodgkin B cell lymphoma is follicular lymphoma, small lymphocytic lymphoma, Burkitt lymphoma, or diffuse large B cell lymphoma.

7. The therapeutic agent according to any one of claims 1 to 4, wherein the blood cancer is relapsed or refractory diffuse large B cell lymphoma.

8. The therapeutic agent according to any one of claims 1 to 4, wherein the blood cancer is chronic lymphocytic leukemia.

9. The therapeutic agent according to any one of claims 1 to 4, wherein the blood cancer is acute lymphoblastic leukemia.

10. The therapeutic agent according to any one of claims 1 to 4, wherein the blood cancer is B cell leukemia.

11. The therapeutic agent according to any one of claims 1 to 4, wherein the blood cancer is Waldenström's macroglobulinemia.

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