Dose-Escalation and Dose-Expansion Study to Evaluate the Safety and Tolerability of Anti-CD7 Allogeneic CAR T-Cells (WU-CART-007) in Patients With CD7+ Hematologic Malignancies

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 Criteria:
Specific criteria apply to T-NHL patients (Cohort A) and leukemia patients (Cohort B):

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.

Inclusion Criteria for Cohort A:

* 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

Inclusion Criteria for Cohort B:

* Patients will have Acute Myeloid Leukemia (AML) (acute leukemia of ambiguous lineage may be enrolled and treated per the AML cohort) 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 C1\^30 OR
    * 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.
* Circulating blast count must be \<30,000/µL by morphology or flow cytometry

Additional inclusion criteria for Cohorts A and B are:

* CD7 positive expression must be demonstrated in malignant cells in bone marrow, peripheral blood, or lymph node biopsies (fresh or archival). 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
* For T-NHL with bone marrow involvement and AML, no hematologic parameters are required. For T-NHL without bone marrow involvement, adequate hematologic parameters are required, including:

  * Hemoglobin ≥ 8 g/dL without transfusion within 7 days
  * Platelets ≥ 20,000 / uL without transfusion within 7 days
  * Absolute neutrophil count ≥ 500 / uL
* 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.
* 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.
* Dose Escalation ONLY: The patient must be considered a candidate for allogeneic hematopoietic stem cell transplantation in the opinion of the treating physician, and an acceptable allogeneic hematopoietic stem cell donor must be identified prior to study enrollment in case a patient experiences toxicity post-infusion that necessitates rescue HSCT. The identified donor may be related, unrelated, haplo-identical or umbilical cord blood, and does not need to be medically cleared prior to screening or dosing. If none of the patients at the RP2D experience severe recurrent infections due to prolonged lymphopenia or otherwise require rescue HSCT (excluding elective HSCT due to treating physician's choice for treatment of underlying disease), subsequent patients will not require identification of a donor prior to enrollment in Dose Expansion.
* Able to understand and willing to sign an IRB approved written informed consent document.

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.