Chimeric Antigen Receptor T Cell Therapy Redirected to CD4 (CD4CAR)as a Second Line Treatment for Chronic Myelomonocytic Leukemia, CMML.

Inclusion Criteria:

1. ≥ 18 years old at the time of informed consent

2. Ability to provide written informed consent and HIPAA authorization

3. Diagnosis of CMML that is CD4+ and is recurrent or refractory to first line standardof care treatment.

4. Creatinine clearance of ≥ 60 ml/min (or otherwise non clinically significant, perstudy investigator)

5. ALT/AST < 3 x ULN

6. Bilirubin < 2 x ULN

7. No supplemental oxygen at rest Note: Pulmonary Function Test (PFT) only required pertreating physician discretion.

8. Adequate cardiac function with EF of ≥50%. This will not have to be repeated ifwithin 45 days of initial assessment

9. Adequate venous access for apheresis and no other contraindications forleukapheresis

Exclusion Criteria:

1. CD4 negative CMML

2. Pregnant or lactating women. The safety of this therapy on unborn children is notknown. Female study participants of reproductive potential (see definition below)must have a negative serum or urine pregnancy test prior to initiation ofconditioning chemotherapy, per research sites' clinical policy

3. Uncontrolled active infection necessitating systemic therapy

4. Active hepatitis B or hepatitis C infection. Active hepatitis C is defined as thehepatitis C antibody is positive while quantitative HCV RNA results exceed the lowerdetection limit Note the following subjects will be eligible:

• Subjects with a history of hepatitis B but have received antiviral therapy andhave non-detectable viral DNA for 6 months prior to enrollment are eligible

• Subjects seropositive for HBS antibodies due to hepatitis B virus vaccine withno signs or active infection (Negative HBs Ag, HBc and HBe Ags) are eligible

• Subjects who had hepatitis C but have received antiviral therapy and show nodetectable hepatitis C virus (HCV) viral RNA for 6 months are eligible

• If hepatitis C antibody test is positive, then patients must be tested for thepresence of antigen by reverse transcription-polymerase chain reaction (RT-PCR)and be hepatitis C virus ribonucleic acid (HCV RNA) negative

5. Concurrent use of systemic glucocorticoids in greater than replacement doses orsteroid dependency defined in rheumatological and pulmonary diseases asuninterrupted corticosteroid intake for more than a year at a dosage of 0.3mg/kg/day or greater, and where the underlying disease worsens on temporary stoppageof steroid therapy, with symptoms of steroids withdrawal (eg, lethargy, headache,weakness, pseudo rheumatism, emotional disturbances, etc) precipitated by thetemporary stoppage unless tapering can occur safely without compromising theunderlying disease, the withdrawal tolerance and can happen in a timeframeappropriate to enroll in this trial without safety concerns Subjects who receive daily corticosteroids in replacement doses can be included inthe study. The replacement doses are defined as following:

6. Hydrocortisone 25mg/day or less

7. Prednisone 10mg/day or less

8. Dexamethasone 4mg or less - Note: Recent or current use of inhaledglucocorticoids is not exclusionary, as this route pertains extremely minimalsystemic penetration

9. Any uncontrolled active medical disorder that would preclude participation asoutlined in the opinion of the treating investigator and/or Principal Investigator

10. HIV infection

11. Subjects who have received or will receive live vaccines within 30 days before thefirst experimental cell treatment. Inactivated seasonal flu vaccination is allowed

12. Subjects with active autoimmune diseases who need systematic treatments (such asdisease modifying agents, corticosteroids and immunosuppressive drugs) during thelast year Note: Replacement therapy (thyroxine, insulin or physiologicalcorticosteroid replacement therapy (up to10 mg of oral daily prednisone orequivalent in hydrocortisone and dexamethasone) to treat adrenal dysfunction orpituitary dysfunction) is not considered as systematic therapy. Subjects who needinhalation corticosteroid therapy can be included in this trial. Subjects withvitiligo or in long-term remission of pediatric asthma or allergic diseases can beincluded in this trial

13. Subjects with a history of mental disorders or drug abuse that may influencetreatment compliance

14. Active malignancy not related to CMML that has required therapy in the last 3 yearsor is not in complete remission. Exceptions to this criterion include successfullytreated non-metastatic basal cell or squamous cell skin carcinoma, or prostatecancer that does not require therapy. Other similar malignant conditions may bediscussed with and permitted by the Principal Investigator CMML patients whotransformed into AML and who were treated back into CMML status are eligible. CMMLpatients who transformed into AML and appropriate AML treatment was unsuccessful inreverting their disease back to CMML status will be treated as AML patients and arenot eligible for the CMML study.

15. Treatment with any investigational cell/gene therapy within the past 6 months

16. Treatment with any investigational anticancer agent within the last 14 days of studyentry or 5 half-lives (whichever is shorter)

Eligibility for Conditioning Chemotherapy:

1. Specific organ function criteria for cardiac, renal, and liver function must besimilar to initial inclusion values

2. Review of co-morbidities to confirm no major changes in health status (examples ofmajor changes include heart attack, stroke, and any major trauma)

3. Planned infusion dose was successfully manufactured and met release criteria

4. Negative pregnancy testing (if applicable)

Eligibility for cd4CAR Infusion Inclusion

1. Afebrile and not receiving antipyretics, and no evidence of active infection. Iffever is attributed to underlying disease, it will not disqualify.

2. Specific organ function criteria for cardiac, renal, and liver function must besimilar to initial inclusion values. The following test does not need repeated: EFif within 6 weeks of initial assessment.

3. If previous history of corticosteroid chemotherapy, subject must be off all butadrenal replacement doses 3 days before the CD4CAR infusion

Exclusion

Note: A subject may still receive the CD4CAR infusion up to 10 days post conditioning chemotherapy as long as they do not meet any of the following at time of infusion:

1. Requirement for supplemental oxygen to keep saturation greater than 95% or presenceof radiographic abnormalities on a clinically indicated chest x-ray that areprogressive.

2. New cardiac arrhythmia not controlled with medical management.

3. Hypotension requiring pressor support.

4. Positive blood cultures for bacteria, fungus, or virus within 48-hours of T cellinfusion.

Contraception and Reproductive Potential Guidelines

Female subjects of reproductive potential (women who have reached menarche or women who have not been post-menopausal for at least 24 consecutive months, i.e., who have had menses within the preceding 24 months, or have not undergone a sterilization procedure [hysterectomy or bilateral oophorectomy]) must have a negative serum or urine pregnancy test prior to conditioning chemotherapy.

Due to the high-risk level of this study, while enrolled, all subjects must agree not to participate in a conception process (e.g., active attempt to become pregnant or to impregnate, sperm donation, in vitro fertilization). Additionally, if participating in sexual activity that could lead to pregnancy, the study subject must agree to use reliable and double barrier methods of contraception from time of consent through at least 90 days after CD4CAR infusion.

Acceptable birth control includes a combination of two of the following methods:

• Condoms (male or female) with or without a spermicidal agent.

• Diaphragm or cervical cap with spermicide

• Intrauterine device (IUD)

• Hormonal-based contraception

Subjects who are not of reproductive potential (women who have been post-menopausal for at least 24 consecutive months or have undergone hysterectomy, salpingotomy, and/or bilateral oophorectomy or men who have documented azoospermia) are eligible without requiring the use of contraception. Acceptable documentation of sterilization, azoospermia, and menopause is specified next:

Written or oral documentation communicated by clinician or clinician's staff of one of the following:

• Physician report/letter

• Operative report or other source documentation in the subject record (a laboratoryreport of azoospermia is required to document successful vasectomy)

• Discharge summary

• Laboratory report of azoospermia

• Follicle stimulating hormone measurement elevated into the menopausal range