xml: <clinical_study>
    <!-- This xml conforms to an XML Schema at:
      https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
    <required_header>
      <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
      <link_text>Link to the current ClinicalTrials.gov record.</link_text>
      <url>https://clinicaltrials.gov/ct2/show/NCT05989204</url>
    </required_header>
    <id_info>
      <org_study_id>UPCC 12423</org_study_id>
      <nct_id>NCT05989204</nct_id>
    </id_info>
    <brief_title>TmCD19-IL18 in CD19+ Cancers</brief_title>
    <official_title>Phase I Trial of TmCD19-IL18 CAR T Cells in Patients With Relapsed or Refractory CD19+ Cancers</official_title>
    <sponsors>
      <lead_sponsor>
        <agency>University of Pennsylvania</agency>
        <agency_class>Other</agency_class>
      </lead_sponsor>
      <collaborator>
        <agency>Kite, A Gilead Company</agency>
        <agency_class>Industry</agency_class>
      </collaborator>
    </sponsors>
    <source>University of Pennsylvania</source>
    <oversight_info>
      <has_dmc>Yes</has_dmc>
      <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
      <is_fda_regulated_device>No</is_fda_regulated_device>
    </oversight_info>
    <brief_summary>
      <textblock>
        This is a Phase I, open-label dose finding study to assess the safety, tolerability,&#xD;
        manufacturing feasibility, pharmacokinetics, and preliminary efficacy of TmCD19-IL18 CAR T&#xD;
        cells in patients with CD19+ cancers. This study will take place in two parts: a Dose-Finding&#xD;
        Phase to determine the maximum tolerate dose (MTD), followed by a Dose Expansion Phase. In&#xD;
        the Dose-Finding Phase, up to 4 total dose levels will be evaluated using a 3+3 dose&#xD;
        escalation design in order to determine the MTD (as defined below). Both safety and&#xD;
        manufacturing feasibility will then be used to identify the dose level that can be progressed&#xD;
        into the Dose Expansion Phase.&#xD;
      </textblock>
    </brief_summary>
    <detailed_description>
      <textblock>
        This study will be initiated with a single disease-specific cohort (Cohort A: Non-Hodgkin&#xD;
        Lymphoma). However, the study design allows for additional disease populations to be&#xD;
        incorporated into the protocol as new cohorts in the future. Each disease-specific cohort&#xD;
        will be evaluated independently for safety and dose-limiting toxicities (DLTs) as follows&#xD;
        Dose escalation will begin with Dose Level 1 as described below.&#xD;
  &#xD;
          -  Dose Level 1 (N = 3 to 6): Subjects will receive a single dose of 7x10⁶ TmCD19-IL18 CAR&#xD;
             T cells via IV infusion administration on Day 0, following lymphodepleting chemotherapy.&#xD;
             This dose levelwill be evaluated as follows:&#xD;
  &#xD;
               -  If 1 DLT/3 subjects occurs, the study will enroll an additional 3 subjects at this&#xD;
                  dose level.&#xD;
  &#xD;
               -  If 0 DLT/3 subjects or 1 DLT/6 subjects occur, the study will advance to Dose Level&#xD;
                  2 (DL2).&#xD;
  &#xD;
               -  In the event that 2 or more DLTs occur at Dose Level 1, enrollment at this dose&#xD;
                  level will be stopped and Dose Level -1 (DL-1) will be opened. In DL-1, subjects&#xD;
                  will receive a de-escalated dose of 3x10⁶ TmCD19-IL18 CAR T cells.&#xD;
  &#xD;
                    -  If 0 DLT/3 or 1 DLT/3 subjects occurs at DL-1, the study will enroll an&#xD;
                       additional 3 subjects at this dose level.&#xD;
  &#xD;
                    -  If ≥ 2 DLTs occur at any time, enrollment at this dose level will be stopped.&#xD;
  &#xD;
          -  Dose Level 2 (N = 3 to 6): Subjects will receive a single fixed dose of 3x10⁷&#xD;
             TmCD19-IL18 CAR T cells via IV infusion on Day 0, following lymphodepleting&#xD;
             chemotherapy. This dose level will be evaluated as follows:&#xD;
  &#xD;
               -  If 1 DLT/3 subjects occurs, the study will enroll an additional 3 subjects at this&#xD;
                  dose level.&#xD;
  &#xD;
               -  If 0 DLT/3 subjects or 1 DLT/6 subjects occur, the study will advance to Dose Level&#xD;
                  3 (DL3).&#xD;
  &#xD;
               -  If 2 DLTs occur at any time, enrollment at this dose level will be stopped. If less&#xD;
                  than 6 subjects were treated at the previous dose level (DL1), additional subjects&#xD;
                  will be enrolled at that dose level to reach a minimum of 6 evaluable subjects for&#xD;
                  MTD determination.&#xD;
  &#xD;
          -  Dose Level 3 (N = 3 to 6): Subjects will receive a single fixed dose of 7x107&#xD;
             TmCD19-IL18 CAR T cells via IV infusion Day 0, following lymphodepleting chemotherapy.&#xD;
             This dose level will be evaluated as follows:&#xD;
  &#xD;
               -  If 1 DLT/3 subjects occurs, the study will enroll an additional 3 subjects at this&#xD;
                  dose level.&#xD;
  &#xD;
               -  If 0 DLT/3 subjects occurs, the study will enroll an additional 3 subjects at this&#xD;
                  dose level.&#xD;
  &#xD;
               -  If 2 DLTs occur at any time, enrollment at this dose level will be stopped. If less&#xD;
                  than 6 subjects were treated at the previous dose level (DL2), additional subjects&#xD;
                  will be enrolled at that dose level to reach a minimum of 6 evaluable subjects for&#xD;
                  MTD determination.&#xD;
  &#xD;
        The DLT observation period is 28 days post-TmCD19-IL18 CAR T cell infusion (Day 0). Formal&#xD;
        DLT evaluations will be performed after the 3rd evaluable subject at each dose level&#xD;
        completes this 28-day DLT monitoring window. These assessments will be performed by the&#xD;
        Clinical PI and Sponsor Medical Director in accordance with the definition in Section 8.1.6&#xD;
        of the protocol. This formal evaluation will trigger a decision regarding dose level&#xD;
        advancement, expansion, or dose de-escalation.&#xD;
  &#xD;
        In order to allow for appropriate monitoring/assessment of toxicities, the TmCD19-IL18 CAR T&#xD;
        cell infusions will be staggered as follows:&#xD;
  &#xD;
          -  The TmCD19-IL18 CAR T cell infusions for the first two subjects treated on this study&#xD;
             must be staggered by at least 28 days.&#xD;
  &#xD;
          -  The 3rd subject at each dose level may not receive TmCD19-IL18 CAR T cells until the 1st&#xD;
             subject at that dose level has completed the 28-day DLT monitoring window.&#xD;
  &#xD;
          -  In the event 1 DLT is identified at a dose level (e.g., 1 DLT/3 evaluable subjects),&#xD;
             formal DLT evaluations must be completed after each additional TmCD19-IL18 CAR T cell&#xD;
             infusion to evaluate potential dose de-escalation rules. As such, subsequent TmCD19-IL18&#xD;
             CAR T cell infusions within that same dose level must be staggered by a minimum of 28&#xD;
             days.&#xD;
  &#xD;
          -  If emergent safety concerns are identified, an ad hoc DLT evaluation may be triggered at&#xD;
             the request of the Clinical PI and/or Sponsor Medical Director.&#xD;
  &#xD;
        Subjects must receive the dose of TmCD19-IL18 CAR T cells as per their dose level assignment&#xD;
        in order to be considered evaluable for dose escalation decisions and MTD determination.&#xD;
        Subjects who do not receive the dose of TmCD19-IL18 CAR T cells as per their dose level&#xD;
        assignment will not be considered evaluable for this purpose and will be replaced. However,&#xD;
        these subjects will still be included in the overall safety analysis, as well as the analyses&#xD;
        of secondary and exploratory endpoints.&#xD;
  &#xD;
        The highest dose at which 0 or 1 DLT occurs in 6 evaluable subjects will be declared the&#xD;
        MTD.The MTD will established for each disease-specific cohort.&#xD;
  &#xD;
        Once the MTD of a disease-specific cohort is officially confirmed, the manufacturing&#xD;
        feasibility at this dose level will also be formally evaluated. Both safety and manufacturing&#xD;
        feasibility will be used to identify the dose level that can be progressed into each&#xD;
        Cohort-Specific Dose Expansion Phase. Specifically, the dose level selected must be at/below&#xD;
        the MTD and feasible from a manufacturing perspective. The sample size for the Expansion&#xD;
        Phase will be calculated based on the total sample size for that disease-specific cohort and&#xD;
        the number of evaluable subjects previously treated in the Dose-Finding Phase prior to&#xD;
        opening the Dose Expansion Phase. Please refer to Section 3.3 of the protocol for complete&#xD;
        information.&#xD;
  &#xD;
        • Cohort-Specific Dose Expansion Phase: Subjects will receive a single fixed dose of&#xD;
        TmCD19-IL18 CAR T cells at the selected dose level via IV infusion Day 0, following&#xD;
        lymphodepleting chemotherapy. Subjects treated under the expansion phase will be evaluated&#xD;
        for overall safety and will not be factored into DLT evaluations/analysis. As such, there are&#xD;
        no protocol-defined staggering requirements under this expansion phase.&#xD;
  &#xD;
        Re-treatment Infusions:&#xD;
  &#xD;
        Subjects who have demonstrated clinical benefit after their initial TmCD19-IL18 CAR T cell&#xD;
        infusion (e.g., minimum disease response of stable disease, etc.) may also be eligible to&#xD;
        receive re-treatment with TmCD19-IL18 CAR T cells at the physician-investigator's discretion.&#xD;
        The TmCD19-IL18 re-treatment dose administered must either be a) the CAR T cell dose that the&#xD;
        subject previously received without DLTs, or b) a CAR T cell that is less than or equal to a&#xD;
        dose level that has been evaluated for safety in ≥ 1 other subject within the same&#xD;
        disease-specific cohort without evidence of DLTs. As re-treatment infusions will not be used&#xD;
        for formal DLT assessments/MTD determination, there are no protocol-defined staggering&#xD;
        requirements.&#xD;
      </textblock>
    </detailed_description>
    <overall_status>Not yet recruiting</overall_status>
    <start_date type="Anticipated">October 1, 2023</start_date>
    <completion_date type="Anticipated">October 1, 2041</completion_date>
    <primary_completion_date type="Anticipated">October 1, 2026</primary_completion_date>
    <phase>Phase 1</phase>
    <study_type>Interventional</study_type>
    <has_expanded_access>No</has_expanded_access>
    <study_design_info>
      <allocation>Non-Randomized</allocation>
      <intervention_model>Parallel Assignment</intervention_model>
      <intervention_model_description>This study will take place in two parts: a Dose-Finding Phase to determine the maximum tolerate dose (MTD), followed by a Dose Expansion Phase. In the Dose-Finding Phase,up to 4 total dose levels will be evaluated using a 3+3 dose escalation design in order to determine the maximum tolerated dose. Both safety and manufacturing feasibility will then be used to identify the dose level that can be progressed into the Dose Expansion Phase.&#xD;
  This study will be initiated with a single disease-specific cohort (Cohort A: Non-Hodgkin Lymphoma). However, the study design allows for additional disease populations to be incorporated into the protocol as new cohorts in the future. Each disease-specific cohort will be evaluated independently for safety and dose-limiting toxicities (DLTs).</intervention_model_description>
      <primary_purpose>Treatment</primary_purpose>
      <masking>None (Open Label)</masking>
    </study_design_info>
    <primary_outcome>
      <measure>Number of subjects with dose limiting toxicities (DLTs)</measure>
      <time_frame>28 days after TMCD19-IL18 CART T cell infusion</time_frame>
    </primary_outcome>
    <primary_outcome>
      <measure>Determination of maximum tolerated dose (MTD)</measure>
      <time_frame>28 days after TMCD19-IL18 CART T cell infusion</time_frame>
    </primary_outcome>
    <primary_outcome>
      <measure>Incidence of Adverse Events as assessed by CTCAE v5.0</measure>
      <time_frame>Up to 15 years</time_frame>
    </primary_outcome>
    <secondary_outcome>
      <measure>Percentage of manufacturing products that meet release criteria</measure>
      <time_frame>Up to 3 years</time_frame>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Overall response rate (ORR)</measure>
      <time_frame>Up to 3 months</time_frame>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Best overall response (BOR)</measure>
      <time_frame>up to one year</time_frame>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Duration of response (DOR)</measure>
      <time_frame>Up to one year</time_frame>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Overall Survival (OS)</measure>
      <time_frame>Up to one year</time_frame>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Progression Free Survival (PFS)</measure>
      <time_frame>Up to one year</time_frame>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Characterize low level disease and B cell assessment in response to TmCD19-IL18 CAR T cells</measure>
      <time_frame>Up to one year</time_frame>
      <description>Polychromatic flow cytometry-based assessment of lymphoma and B cells</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Characterize low level disease and B cell assessment in response to TmCD19-IL18 CAR T cells</measure>
      <time_frame>Up to one year</time_frame>
      <description>Presence or absence of malignant B cells by Next-Generation Immunoglobulin Heavy Chain Sequencing (NGIS)</description>
    </secondary_outcome>
    <number_of_arms>4</number_of_arms>
    <enrollment type="Anticipated">24</enrollment>
    <condition>Non Hodgkin Lymphoma</condition>
    <arm_group>
      <arm_group_label>NHL Dose Level 1</arm_group_label>
      <arm_group_type>Experimental</arm_group_type>
      <description>7x10(6) huCART19-IL18 cells administered as a single intravenous (IV) infusion</description>
    </arm_group>
    <arm_group>
      <arm_group_label>NHL Dose Level -1</arm_group_label>
      <arm_group_type>Experimental</arm_group_type>
      <description>3x10(6) huCART19-IL18 cells administered as a single intravenous (IV) infusion</description>
    </arm_group>
    <arm_group>
      <arm_group_label>NHL Dose Level 2</arm_group_label>
      <arm_group_type>Experimental</arm_group_type>
      <description>3x10(7) huCART19-IL18 cells administered as a single intravenous (IV) infusion</description>
    </arm_group>
    <arm_group>
      <arm_group_label>NHL Dose Level 3</arm_group_label>
      <arm_group_type>Experimental</arm_group_type>
      <description>7x10(7) huCART19-IL18 cells administered as a single intravenous (IV) infusion</description>
    </arm_group>
    <intervention>
      <intervention_type>Biological</intervention_type>
      <intervention_name>TMhuCART19-IL18</intervention_name>
      <description>autologous Chimeric Antigen Receptor (CAR) T cells directed against the human CD19 antigen that also express human Interleukin 18 (IL-18)</description>
      <arm_group_label>NHL Dose Level -1</arm_group_label>
      <arm_group_label>NHL Dose Level 1</arm_group_label>
      <arm_group_label>NHL Dose Level 2</arm_group_label>
      <arm_group_label>NHL Dose Level 3</arm_group_label>
    </intervention>
    <eligibility>
      <criteria>
        <textblock>
          1. Signed informed consent form&#xD;
  &#xD;
            2. Documentation of CD19 expression on malignant cells by flow cytometry/IHC at the&#xD;
               Hospital ofthe University of Pennsylvania.&#xD;
  &#xD;
               a. Cohort A (NHL): Within 6 months of physician-investigator confirmation of&#xD;
               eligibility aslong as there has been no intervening CD19 directed therapy since&#xD;
               expression confirmed.Results outside of this window may be used, if there is no&#xD;
               accessible tumor site and the subject did not receive intervening CD19 directed&#xD;
               therapy since CD19 expression was confirmed.&#xD;
  &#xD;
            3. Patients with relapsed disease after prior allogeneic SCT must meet the following&#xD;
               criteria:&#xD;
  &#xD;
               a. Have no active GVHD and require no immuno-suppressionb. Are more than 6 months from&#xD;
               transplant at the time of physician-investigator confirmation of eligibility&#xD;
  &#xD;
            4. Adequate organ function defined as:&#xD;
  &#xD;
                 1. Estimated creatinine clearance &gt; 35 mL/min and not on dialysis&#xD;
  &#xD;
                 2. ALT/AST ≤ 3x upper limit of normal range&#xD;
  &#xD;
                 3. Direct bilirubin ≤ 2.0 mg/dl, unless the subject has Gilbert's syndrome (≤3.0&#xD;
                    mg/dl)&#xD;
  &#xD;
                 4. Must have a minimum level of pulmonary reserve defined as ≤ Grade 1 dyspnea and&#xD;
                    pulse oxygen &gt; 92% on room air&#xD;
  &#xD;
                 5. Left Ventricle Ejection Fraction (LVEF) ≥ 40% confirmed by ECHO&#xD;
  &#xD;
            5. Evidence of active disease within 12 weeks of physician-investigator confirmation of&#xD;
               eligibility.&#xD;
  &#xD;
            6. Male or female age ≥ 18 years.&#xD;
  &#xD;
            7. ECOG Performance Status that is either 0 or 1.&#xD;
  &#xD;
            8. Disease-specific criteria:&#xD;
  &#xD;
               a. Cohort A (NHL): i. Patients with any of the following diagnoses: Diffuse Large&#xD;
               B-cell Lymphoma not otherwise specified (DLBCL NOS), germinal center or activated&#xD;
               B-cell types; Primary Cutaneous DLBCL; Primary Mediastinal (thymic) Large B-cell&#xD;
               Lymphoma; ALK+ Anaplastic Large B-cell Lymphoma; High-Grade B-cell Lymphoma with MYC&#xD;
               and BCL2 and/or BCL6 rearrangements (i.e., &quot;Double or Triple Hit&quot;); High-grade B-cell&#xD;
               Lymphoma, NOS; T-cell Rich B-cell Lymphoma; Transformed Follicular Lymphoma; or any&#xD;
               aggressive B-cell lymphoma arising from indolent lymphoma.&#xD;
  &#xD;
          1. Patients must have either relapsed after, or be ineligible for, prior CAR T cell&#xD;
          therapy, and meet one of the following criteria:&#xD;
  &#xD;
            1. Relapsed/refractory disease after at least 2 prior lines of appropriate therapy; OR&#xD;
  &#xD;
            2. Relapsed/refractory disease after autologous SCT; OR&#xD;
  &#xD;
            3. Relapsed/refractory disease after allogeneic SCT. ii. Follicular lymphoma&#xD;
  &#xD;
                 1. Patients must have either relapsed after, or be ineligible for, prior commercial&#xD;
                    CAR T cell therapy; AND&#xD;
  &#xD;
                 2. Received at least 2 prior lines of appropriate therapy (not including single&#xD;
                    agent monoclonal antibody therapy) and progressed within 2 years after second or&#xD;
                    higher line of therapy.&#xD;
  &#xD;
          iii. Mantle cell lymphoma&#xD;
  &#xD;
          1. Patients must have either failed standard of care CAR T cell therapy (e.g., Tecartus™,&#xD;
          etc) or other investigational CAR T cell product, OR be ineligible for standard of care&#xD;
          Tecartus™; and2. Patients must also meet one of the following criteria:&#xD;
  &#xD;
            1. Relapsed/refractory disease after at least 2 prior lines of appropriate therapy,&#xD;
               including a BTK inhibitor. Single-agent monoclonal antibody therapy does not count&#xD;
               towards prior lines of therapy; OR&#xD;
  &#xD;
            2. Relapsed/refractory disease after prior autologous SCT; OR&#xD;
  &#xD;
            3. Relapsed/refractory disease after prior allogeneic SCT. iv. Marginal Zone Lymphoma 1.&#xD;
               Patients must have received at least 2 prior lines of appropriate therapy which&#xD;
               includes a BTK inhibitor (not including single agent monoclonal antibody therapy).&#xD;
  &#xD;
          Exclusion Criteria:&#xD;
  &#xD;
            1. Active hepatitis B, active hepatitis C, or other active, uncontrolled infection.&#xD;
  &#xD;
            2. Class III/IV cardiovascular disability according to the New York Heart Association&#xD;
               Classification (see Appendix 5 of the protocol).&#xD;
  &#xD;
            3. Clinically apparent arrhythmia or arrhythmias that are not stable on medical&#xD;
               management within two weeks of physician-investigator confirmation of eligibility.&#xD;
  &#xD;
            4. Active acute or chronic GVHD requiring systemic therapy.&#xD;
  &#xD;
            5. Dependence on systemic steroids or immuno-suppressant medications. For additional&#xD;
               details regarding use of steroid and immuno-suppressant medications, please see&#xD;
               Section 5.5 of the protocol.&#xD;
  &#xD;
            6. Receipt of prior huCART19-IL18 therapy.&#xD;
  &#xD;
            7. CNS disease as defined by disease-cohort as follows:&#xD;
  &#xD;
               a. Cohort A: Active CNS disease. Note: Patients with a history of CNS involvement that&#xD;
               was successfully treated are eligible. A CNS evaluation is only required for&#xD;
               eligibility if a subject is experiencing signs/symptoms of CNS involvement.&#xD;
  &#xD;
            8. Pregnant or nursing (lactating) patients. Participants of reproductive potential must&#xD;
               agree to use acceptable birth control methods, as described in protocol Section 4.3 of&#xD;
               the protocol.&#xD;
  &#xD;
            9. Patients with a known history or prior diagnosis of optic neuritis or other&#xD;
               immunologic or inflammatory disease affecting the central nervous system, and&#xD;
               unrelated to their cancer or previous cancer treatment.&#xD;
  &#xD;
           10. Active autoimmune disease requiring systemic immuno-suppressive treatment equivalent&#xD;
               to ≥10mg of prednisone. Patients with autoimmune neurologic diseases (such as MS) will&#xD;
               beexcluded.&#xD;
        </textblock>
      </criteria>
      <gender>All</gender>
      <minimum_age>18 Years</minimum_age>
      <maximum_age>N/A</maximum_age>
      <healthy_volunteers>No</healthy_volunteers>
    </eligibility>
    <verification_date>August 2023</verification_date>
    <study_first_submitted>August 2, 2023</study_first_submitted>
    <study_first_submitted_qc>August 2, 2023</study_first_submitted_qc>
    <study_first_posted type="Actual">August 14, 2023</study_first_posted>
    <last_update_submitted>August 2, 2023</last_update_submitted>
    <last_update_submitted_qc>August 2, 2023</last_update_submitted_qc>
    <last_update_posted type="Actual">August 14, 2023</last_update_posted>
    <responsible_party>
      <responsible_party_type>Sponsor</responsible_party_type>
    </responsible_party>
    <condition_browse>
      <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
      <mesh_term>Lymphoma, Non-Hodgkin</mesh_term>
    </condition_browse>
    <!-- Results have not yet been posted for this study                                          -->
  </clinical_study>
  
  
text: download date: ClinicalTrials.gov processed this data on September 20, 2023
  link text: Link to the current ClinicalTrials.gov record.
  url: https://clinicaltrials.gov/ct2/show/NCT05989204
  org study id: UPCC 12423
  nct id: NCT05989204
  lead sponsor: 
  collaborator: 
  has dmc: Yes
  is fda regulated drug: Yes
  is fda regulated device: No
  This is a Phase I, open-label dose finding study to assess the safety, tolerability,
        manufacturing feasibility, pharmacokinetics, and preliminary efficacy of TmCD19-IL18 CAR T
        cells in patients with CD19+ cancers. This study will take place in two parts: a Dose-Finding
        Phase to determine the maximum tolerate dose (MTD), followed by a Dose Expansion Phase. In
        the Dose-Finding Phase, up to 4 total dose levels will be evaluated using a 3+3 dose
        escalation design in order to determine the MTD (as defined below). Both safety and
        manufacturing feasibility will then be used to identify the dose level that can be progressed
        into the Dose Expansion Phase.
  This study will be initiated with a single disease-specific cohort (Cohort A: Non-Hodgkin
        Lymphoma). However, the study design allows for additional disease populations to be
        incorporated into the protocol as new cohorts in the future. Each disease-specific cohort
        will be evaluated independently for safety and dose-limiting toxicities (DLTs) as follows
        Dose escalation will begin with Dose Level 1 as described below.
  
          -  Dose Level 1 (N = 3 to 6): Subjects will receive a single dose of 7x10⁶ TmCD19-IL18 CAR
             T cells via IV infusion administration on Day 0, following lymphodepleting chemotherapy.
             This dose levelwill be evaluated as follows:
  
               -  If 1 DLT/3 subjects occurs, the study will enroll an additional 3 subjects at this
                  dose level.
  
               -  If 0 DLT/3 subjects or 1 DLT/6 subjects occur, the study will advance to Dose Level
                  2 (DL2).
  
               -  In the event that 2 or more DLTs occur at Dose Level 1, enrollment at this dose
                  level will be stopped and Dose Level -1 (DL-1) will be opened. In DL-1, subjects
                  will receive a de-escalated dose of 3x10⁶ TmCD19-IL18 CAR T cells.
  
                    -  If 0 DLT/3 or 1 DLT/3 subjects occurs at DL-1, the study will enroll an
                       additional 3 subjects at this dose level.
  
                    -  If ≥ 2 DLTs occur at any time, enrollment at this dose level will be stopped.
  
          -  Dose Level 2 (N = 3 to 6): Subjects will receive a single fixed dose of 3x10⁷
             TmCD19-IL18 CAR T cells via IV infusion on Day 0, following lymphodepleting
             chemotherapy. This dose level will be evaluated as follows:
  
               -  If 1 DLT/3 subjects occurs, the study will enroll an additional 3 subjects at this
                  dose level.
  
               -  If 0 DLT/3 subjects or 1 DLT/6 subjects occur, the study will advance to Dose Level
                  3 (DL3).
  
               -  If 2 DLTs occur at any time, enrollment at this dose level will be stopped. If less
                  than 6 subjects were treated at the previous dose level (DL1), additional subjects
                  will be enrolled at that dose level to reach a minimum of 6 evaluable subjects for
                  MTD determination.
  
          -  Dose Level 3 (N = 3 to 6): Subjects will receive a single fixed dose of 7x107
             TmCD19-IL18 CAR T cells via IV infusion Day 0, following lymphodepleting chemotherapy.
             This dose level will be evaluated as follows:
  
               -  If 1 DLT/3 subjects occurs, the study will enroll an additional 3 subjects at this
                  dose level.
  
               -  If 0 DLT/3 subjects occurs, the study will enroll an additional 3 subjects at this
                  dose level.
  
               -  If 2 DLTs occur at any time, enrollment at this dose level will be stopped. If less
                  than 6 subjects were treated at the previous dose level (DL2), additional subjects
                  will be enrolled at that dose level to reach a minimum of 6 evaluable subjects for
                  MTD determination.
  
        The DLT observation period is 28 days post-TmCD19-IL18 CAR T cell infusion (Day 0). Formal
        DLT evaluations will be performed after the 3rd evaluable subject at each dose level
        completes this 28-day DLT monitoring window. These assessments will be performed by the
        Clinical PI and Sponsor Medical Director in accordance with the definition in Section 8.1.6
        of the protocol. This formal evaluation will trigger a decision regarding dose level
        advancement, expansion, or dose de-escalation.
  
        In order to allow for appropriate monitoring/assessment of toxicities, the TmCD19-IL18 CAR T
        cell infusions will be staggered as follows:
  
          -  The TmCD19-IL18 CAR T cell infusions for the first two subjects treated on this study
             must be staggered by at least 28 days.
  
          -  The 3rd subject at each dose level may not receive TmCD19-IL18 CAR T cells until the 1st
             subject at that dose level has completed the 28-day DLT monitoring window.
  
          -  In the event 1 DLT is identified at a dose level (e.g., 1 DLT/3 evaluable subjects),
             formal DLT evaluations must be completed after each additional TmCD19-IL18 CAR T cell
             infusion to evaluate potential dose de-escalation rules. As such, subsequent TmCD19-IL18
             CAR T cell infusions within that same dose level must be staggered by a minimum of 28
             days.
  
          -  If emergent safety concerns are identified, an ad hoc DLT evaluation may be triggered at
             the request of the Clinical PI and/or Sponsor Medical Director.
  
        Subjects must receive the dose of TmCD19-IL18 CAR T cells as per their dose level assignment
        in order to be considered evaluable for dose escalation decisions and MTD determination.
        Subjects who do not receive the dose of TmCD19-IL18 CAR T cells as per their dose level
        assignment will not be considered evaluable for this purpose and will be replaced. However,
        these subjects will still be included in the overall safety analysis, as well as the analyses
        of secondary and exploratory endpoints.
  
        The highest dose at which 0 or 1 DLT occurs in 6 evaluable subjects will be declared the
        MTD.The MTD will established for each disease-specific cohort.
  
        Once the MTD of a disease-specific cohort is officially confirmed, the manufacturing
        feasibility at this dose level will also be formally evaluated. Both safety and manufacturing
        feasibility will be used to identify the dose level that can be progressed into each
        Cohort-Specific Dose Expansion Phase. Specifically, the dose level selected must be at/below
        the MTD and feasible from a manufacturing perspective. The sample size for the Expansion
        Phase will be calculated based on the total sample size for that disease-specific cohort and
        the number of evaluable subjects previously treated in the Dose-Finding Phase prior to
        opening the Dose Expansion Phase. Please refer to Section 3.3 of the protocol for complete
        information.
  
        • Cohort-Specific Dose Expansion Phase: Subjects will receive a single fixed dose of
        TmCD19-IL18 CAR T cells at the selected dose level via IV infusion Day 0, following
        lymphodepleting chemotherapy. Subjects treated under the expansion phase will be evaluated
        for overall safety and will not be factored into DLT evaluations/analysis. As such, there are
        no protocol-defined staggering requirements under this expansion phase.
  
        Re-treatment Infusions:
  
        Subjects who have demonstrated clinical benefit after their initial TmCD19-IL18 CAR T cell
        infusion (e.g., minimum disease response of stable disease, etc.) may also be eligible to
        receive re-treatment with TmCD19-IL18 CAR T cells at the physician-investigator's discretion.
        The TmCD19-IL18 re-treatment dose administered must either be a) the CAR T cell dose that the
        subject previously received without DLTs, or b) a CAR T cell that is less than or equal to a
        dose level that has been evaluated for safety in ≥ 1 other subject within the same
        disease-specific cohort without evidence of DLTs. As re-treatment infusions will not be used
        for formal DLT assessments/MTD determination, there are no protocol-defined staggering
        requirements.
  allocation: Non-Randomized
  intervention model: Parallel Assignment
  intervention model description: This study will take place in two parts: a Dose-Finding Phase to determine the maximum tolerate dose (MTD), followed by a Dose Expansion Phase. In the Dose-Finding Phase,up to 4 total dose levels will be evaluated using a 3+3 dose escalation design in order to determine the maximum tolerated dose. Both safety and manufacturing feasibility will then be used to identify the dose level that can be progressed into the Dose Expansion Phase.
  This study will be initiated with a single disease-specific cohort (Cohort A: Non-Hodgkin Lymphoma). However, the study design allows for additional disease populations to be incorporated into the protocol as new cohorts in the future. Each disease-specific cohort will be evaluated independently for safety and dose-limiting toxicities (DLTs).
  primary purpose: Treatment
  masking: None (Open Label)
  measure: Number of subjects with dose limiting toxicities (DLTs)
  time frame: 28 days after TMCD19-IL18 CART T cell infusion
  measure: Determination of maximum tolerated dose (MTD)
  time frame: 28 days after TMCD19-IL18 CART T cell infusion
  measure: Incidence of Adverse Events as assessed by CTCAE v5.0
  time frame: Up to 15 years
  measure: Percentage of manufacturing products that meet release criteria
  time frame: Up to 3 years
  measure: Overall response rate (ORR)
  time frame: Up to 3 months
  measure: Best overall response (BOR)
  time frame: up to one year
  measure: Duration of response (DOR)
  time frame: Up to one year
  measure: Overall Survival (OS)
  time frame: Up to one year
  measure: Progression Free Survival (PFS)
  time frame: Up to one year
  measure: Characterize low level disease and B cell assessment in response to TmCD19-IL18 CAR T cells
  time frame: Up to one year
  description: Polychromatic flow cytometry-based assessment of lymphoma and B cells
  measure: Characterize low level disease and B cell assessment in response to TmCD19-IL18 CAR T cells
  time frame: Up to one year
  description: Presence or absence of malignant B cells by Next-Generation Immunoglobulin Heavy Chain Sequencing (NGIS)
  arm group label: NHL Dose Level 1
  arm group type: Experimental
  description: 7x10(6) huCART19-IL18 cells administered as a single intravenous (IV) infusion
  arm group label: NHL Dose Level -1
  arm group type: Experimental
  description: 3x10(6) huCART19-IL18 cells administered as a single intravenous (IV) infusion
  arm group label: NHL Dose Level 2
  arm group type: Experimental
  description: 3x10(7) huCART19-IL18 cells administered as a single intravenous (IV) infusion
  arm group label: NHL Dose Level 3
  arm group type: Experimental
  description: 7x10(7) huCART19-IL18 cells administered as a single intravenous (IV) infusion
  intervention type: Biological
  intervention name: TMhuCART19-IL18
  description: autologous Chimeric Antigen Receptor (CAR) T cells directed against the human CD19 antigen that also express human Interleukin 18 (IL-18)
  arm group label: NHL Dose Level -1
  arm group label: NHL Dose Level 1
  arm group label: NHL Dose Level 2
  arm group label: NHL Dose Level 3
  criteria: 
  gender: All
  minimum age: 18 Years
  maximum age: N/A
  healthy volunteers: No
  responsible party type: Sponsor
  mesh term: Lymphoma, Non-Hodgkin