Overview

Effective treatment options for relapsed/refractory acute myeloid leukemia (AML) and T-cell non-Hodgkin lymphoma (T-NHL) represent a significant unmet medical need. CAR T therapy has offered durable remissions and potential cures in some forms of hematologic malignancy, including B-cell acute lymphoblastic leukemia. In AML, however, CAR T approaches have been limited by the lack of suitable antigens, as most myeloid markers are shared with normal hematopoietic stem cells and targeting of these antigens by CAR T therapy leads to undesirable hematologic toxicity. Similarly, T-NHL has not yet benefited from CAR T therapy due to a lack of suitable markers. One potential therapeutic target is CD7, which is expressed normally on mature T-cells and NK-cells but is also aberrantly expressed on ~30% of acute myeloid leukemias. CAR T therapy for patients with CD7+ AML and T-NHL will potentially offer a new therapeutic option which has a chance of offering durable benefit.

WU-CART-007 is a CD7-directed, genetically modified, allogeneic, fratricide-resistant chimeric antigen receptor (CAR) T-cell product for the treatment of CD7+ hematologic malignancies. These cells have two key changes from conventional, autologous CAR T-cells. First, because CD7 is present on normal T-cells including conventional CAR T products, CD7 is deleted from WU CART-007. This allows for targeting of CD7 without the risk of fratricide (killing of WU-CART-007 cells by other WU-CART-007 cells). Second, the T cell receptor alpha constant (TRAC) is also deleted. This makes WU CART 007 cells incapable of recognizing antigens other than CD7 and allows for the use of an allogeneic product without causing Graft-versus-Host-Disease (GvHD).

Eligibility

Inclusion Criteria:

Specific criteria apply to each disease subtype with T-NHL and AML cohorts.

        In general, all patients must have CD7 expression and confirmed diagnoses of T-cell non
        Hodgkin lymphoma or acute myeloid leukemia (any subtype except acute promyelocytic
        leukemia) according to World Health Organization (WHO) classification29, and have relapsed
        or refractory disease.
        For the T-NHL cohort, patients will have T-cell non-Hodgkin lymphoma with relapsed or
        refractory disease defined as one of the following:
        -Relapsed or refractory after at least 2 or more prior lines of therapy (for patients with
        anaplastic large cell lymphoma, they must have prior therapy brentuximab vedotin). For
        patients with T-PLL, only 1 or more prior line of therapy is required.
        OR
          -  Relapsed after autologous or allogeneic hematopoietic cell transplant.
          -  Permissible T-cell NHL subtypes will include:
               -  angioimmunoblastic T-cell lymphoma (AITL)
               -  enteropathy-associated T-cell lymphoma (EATL)
               -  monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL)
               -  peripheral T-cell lymphoma (PTCL) NOS
               -  anaplastic large cell lymphoma (ALCL)
               -  adult T-cell leukemia/lymphoma
               -  T-cell prolymphocytic leukemia (T-PLL)
               -  extranodal NK/T cell lymphoma
               -  transformed mycosis fungoides/Sezary Syndrome
               -  primary cutaneous gamma/delta T-cell lymphoma
               -  hepatosplenic T cell lymphoma
        For the AML cohort, patients will have Acute Myeloid Leukemia with relapsed or refractory
        disease unlikely to benefit from standard therapy defined as one of the following:
        -Primary refractory AML defined as:
          -  Minor or no response to intensive induction chemotherapy with more than 15% blasts and
             less than 50% proportional reduction in blast percentage after C130
          -  Absence of morphological CR/CRi following either:
               -  2 cycles of intensive induction chemotherapy
               -  2 cycles of HMA plus venetoclax, or
               -  4 total cycles of an HMA
        OR
        -Morphologic relapse (≥ 5% bone marrow blasts) with either:
          -  Initial CR duration < 1 year
          -  Prior unsuccessful salvage attempt or allogeneic HCT
          -  2nd relapse or higher
        OR
        -Disease progression while on treatment with HMA+/-venetoclax for MDS/AML
        Patients with a susceptible FLT3, IDH1 or IDH2 mutation should be resistant or intolerant
        to an agent targeting the specific mutation or otherwise be determined to be ineligible to
        receive a targeted agent by their treating physician.
        Additional inclusion criteria for both cohorts are:
          -  CD7 positive expression must be demonstrated in malignant cells in bone marrow,
             peripheral blood, or lymph node biopsies (fresh or archival) by Washington University
             Pathology lab. For both dose escalation and dose-expansion, any qualitative expression
             of CD7 will be permitted.
          -  Age ≥ 18 years of age
          -  Eastern Cooperative Oncology Group Performance Status ≤ 2
          -  Adequate organ function as defined below:
               -  Total bilirubin ≤ 2x ULN (unless the patient has Grade 1 bilirubin elevation due
                  to Gilbert's disease or a similar syndrome involving slow conjugation of
                  bilirubin).
               -  AST(SGOT) and ALT(SGPT) ≤ 5x ULN
               -  Creatinine within normal institutional limits OR creatinine clearance ≥ 30
                  mL/min/1.73 m2 by Cockcroft-Gault Formula
               -  Oxygen saturation ≥ 90% on room air
               -  Ejection fraction ≥ 40% confirmed by echocardiogram or MUGA
          -  The effects of WU-CART-007 on the developing human fetus are unknown. For this reason,
             women of childbearing potential and male patients (along with their female partners)
             are required to use two forms of acceptable contraception, including one barrier
             method, during participation in the study and for 12 months following the last dose of
             WU-CART-007. Should a woman (or the female partner of a male patient) become pregnant
             or suspect she is pregnant while participating in this study, she must inform her
             treating physician immediately.
          -  Able to understand and willing to sign an IRB approved written informed consent
             document.
          -  For AML patients, circulating blast count must be <30,000/µL by morphology or flow
             cytometry (cytoreductive therapies including leukapheresis or hydroxyurea are allowed
             as defined by protocol)
          -  Patients must have no other effective standard of care therapy options, and patients
             must be unwilling or unable to travel to another site for treatment.
        Exclusion Criteria:
        Patients will be excluded from study entry for any of the following:
          -  Received systemic anticancer therapy (including investigational therapy) or
             radiotherapy < 28 days or 5 half-lives, whichever is shorter, prior to the start of
             lymphodepleting chemotherapy with the exception of bridging treatment as defined by
             protocol.
          -  Received any T-cell lytic or toxic antibody (e.g., alemtuzumab) within 8 weeks prior
             to lymphodepleting chemotherapy.
          -  Subjects who have received a prior allogeneic HCT are excluded if any of the following
             criteria are present:
               -  < 100 days post alloHCT
               -  < 6 weeks from prior donor leukocyte infusion
               -  Presence of acute or extensive chronic GVHD requiring systemic immunosuppression
                  except for prednisone ≤ 10 mg or equivalent.
               -  < 28 days from last dose of systemic immunosuppressive therapy (eg. calcineurin
                  inhibitors, immunosuppressive antibodies, mycophenolate mofetil, ruxolitinib,
                  ibrutinib) except for prednisone ≤ 10 mg or equivalent.
          -  Previous treatment with any anti-CD7 directed therapy.
          -  Known hypersensitivity to one or more of the study agents.
          -  Active or latent Hepatitis B or active Hepatitis C without previous curative
             treatment.
          -  Confirmed HIV infection.
          -  History of concurrent second cancers requiring active, ongoing systemic treatment with
             the exception of adjuvant hormonal therapy for breast or prostate cancer.
          -  Pregnant and/or breastfeeding. Women of childbearing potential must have a negative
             serum or urine pregnancy test at time of enrollment and within 7 days of starting
             lymphodepleting chemotherapy.
          -  Serious active infection or another serious underlying medical condition that in the
             opinion of the treating physician would impair the ability of the patient to receive
             protocol treatment including, but not limited to symptomatic congestive heart failure,
             unstable angina pectoris, uncontrolled cardiac arrhythmia or serious, unstable
             neurologic symptoms.
          -  Symptomatic, uncontrolled hypotension.