E7 TCR T Cell Induction Immunotherapy for Stage IIB-IVA Cervical Cancer
E7 TCR T Cell Induction Immunotherapy for Stage IIB-IVA Cervical Cancer
Background:

 More than 12,000 cases of cervical cancer are diagnosed in the United States each year. A new
 therapy has been developed that involves taking white blood cells from a person, genetically
 modifying the cells in a lab so they recognize cancer, and then giving the cells back to the
 person. Researchers want to see if this therapy can help people with cervical cancer.

 Objective:

 To find out if people with Stage IIB-IVA cervical cancer can safely be given E7 TCR T cells
 before they get standard treatment.

 Eligibility:

 People age 18 and older who have Stage IIB-IVA cervical cancer

 Design:

 Participants will be screened under a separate protocol. Tests will include:

 -  Physical exam

 -  Medicine review

 -  Blood tests

 -  Pregnancy test (if needed)

 -  Vein assessment

 -  Tumor sample or biopsy

 -  Electrocardiogram (to record the heart s electrical activity)

 -  Imaging scans, x-rays, and/or endoscopy

 -  Heart and/or lung tests.

 Some screening tests will be repeated during the study.

 Participants will undergo leukapheresis. For this, blood is removed through a needle in the
 arm. A machine removes the white blood cells. The rest of the blood is returned through a
 needle in the other arm. Participants may need to have a large catheter inserted into a vein.

 Participants will stay at the hospital for 2-3 weeks. They will get chemotherapy drugs. They
 will get the E7 TCR T cells as an intravenous infusion. They will get the drug aldesleukin.

 Participants will visit the NIH 3 and 6 weeks after treatment. They will be contacted yearly
 for 5 years. They will be asked to participate in long-term follow-up for 15 years....
Background:

 -  Cervical cancer is the third most common cause of death among women with gynecologic
 cancers in the United States. Worldwide, cervical cancer accounts for nearly 300,000
 deaths annually.

 -  Virtually all cases of cervical cancer result from chronic infection with high-risk
 human papillomavirus (HPV), the most common type being HPV16.

 -  The treatment of locally advanced cervical cancer consists of chemoradiation +/-
 extended field radiation therapy. Participants with FIGO (revised 2018) stage III-IVA
 have the worse prognosis with approximately 50% of the participants dying from their
 disease within 5 years.

 -  Induction chemotherapy is an active area of study in this type of cancer. The aim of
 induction therapy is to reduce the risk of disease recurrence and improve overall
 survival.

 -  E7 TCR T cells, administered as a single infusion, have demonstrated safety and clinical
 activity in advanced, treatment-refractory metastatic HPV+ cancers.

 Objectives:

 -To determine the feasibility of induction E7 TCR T cell therapy for FIGO (2018) stage
 IIB-IVA, HPV16+ cervical cancer

 Eligibility:

 -  Participants greater than or equal to 18 years old with FIGO (2018) stage IIB-IVA
 cervical cancer.

 -  The cancer must be HPV16+ and participant must be HLA-A*02:01+.

 -  Participants must be treatment-naive (i.e., no prior local or systemic treatment,
 including radiation; prior LEEP procedure or cone biopsy is allowed).

 Design:

 -  This is a single arm, pilot study, testing the feasibility of induction E7 TCR T cell
 therapy.

 -  Participants will receive a conditioning regimen of cyclophosphamide and fludarabine, a
 single infusion of E7 TCR T cells, and systemic aldesleukin.

 -  Participants will be referred for standard of care definitive therapy (i.e.,
 chemoradiation +/- extended field radiation therapy) within 6 weeks after infusion of E7
 TCR T cells.
-INCLUSION CRITERIA:

 1. Participants with histologically or cytologically confirmed carcinoma of the cervix
 that has not been treated, with clinical staging as follows:

 -  Lead-in safety cohort: FIGO stage IIIC-IVA (2018 International FIGO Staging
 System)

 -  After lead-in safety cohort: FIGO stage IIB-IVA (2018 International FIGO Staging
 System)

 2. HPV16+ tumor and HLA-A*02:01+ HLA type. Note: HLA-A*02 is also acceptable for
 enrollment but not for treatment.

 3. Measurable disease by RECIST 1.1 criteria or PERCIST (if not eligible by RECIST 1.1).

 4. Age 18 years. Because no dosing or adverse event data are currently available on the
 use of E7 TCR T cells in participants <18 years of age, children are excluded from
 this study. Note: This age range is consistent with the age of participants with the
 disease being studied.

 5. ECOG performance status 0 or 1.

 6. Women of child-bearing potential must have a negative pregnancy test because E7 TCR T
 cells have unknown potential for teratogenic or abortifacient effects. Women of child-
 bearing potential are defined as all women who are not post-menopausal or who have not
 had a hysterectomy. Note: Postmenopausal will be defined in this study as women over
 the age of 55 who have not had a menstrual period in at least 1 year.

 7. The effects of E7 TCR T cells on the developing human fetus are unknown. For this
 reason and because the chemotherapy agents used in this trial are known to be
 teratogenic, women of child-bearing potential must agree to use adequate contraception
 (e.g., intrauterine device, hormonal or barrier method of birth control; abstinence;
 tubal ligation or vasectomy) prior to study entry and for four months after treatment.
 Should a woman become pregnant or suspect she is pregnant while she is participating
 in this study, she should inform her treating physician immediately.

 8. Seronegative for HIV antibody. The experimental treatment being evaluated in this
 protocol depends on an intact immune system. Participants who are HIV seropositive can
 have decreased immune-competence and thus be less responsive to the experimental
 treatment.

 9. Seronegative for hepatitis B antigen and hepatitis C antibody. If hepatitis C antibody
 test is positive, then the participant must be tested for the presence of antigen by
 RT-PCR and be HCV RNA negative.

 10. Must be willing to participate in Gene Therapy Long Term Follow up Protocol (20C0051),
 which will follow participants for up to 15 years per Food and Drug
 Administration(FDA) requirements.

 11. Participants must have organ and marrow function as defined below:

 -  leukocytes >=3,000/mcL

 -  absolute neutrophil count >=1,500/mcL

 -  platelets >=100,000/mcL

 -  hemoglobin >=9.0 g/dL

 -  total bilirubin within normal institutional limits except in participants with
 Gilbert s Syndrome who must have a total bilirubin < 3.0 mg/dL

 -  AST(SGOT)/ALT(SGPT) Serum ALT/AST < 2.5X ULN

 -  creatinine clearance Calculated creatinine clearance (CrCl) >=50 mL/min/1.73 m^2
 for participants with creatinine levels above institutional normal (by the
 Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation)

 12. Ability of subject to understand and the willingness to sign a written informed
 consent document.

 EXCLUSION CRITERIA:

 1. Previous treatment for invasive cervical cancer including:

 -  Chemotherapy or other systemic treatments

 -  Radiation therapy

 -  Hysterectomy (prior LEEP procedure or cone biopsy is allowed)

 2. Participants who are receiving any other investigational agents.

 3. History of severe allergic reactions attributed to compounds of similar chemical or
 biologic composition to agents used in study.

 4. Uncontrolled intercurrent illness including, but not limited to, ongoing or active
 infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
 arrhythmia, or psychiatric illness/social situations at the time of treatment that
 would limit compliance with study requirements.

 5. Because there is an unknown but potential risk for adverse events in nursing infants
 secondary to treatment of the mother with E7 TCR T cells, breastfeeding should be
 discontinued if the mother is treated with E7 TCR T cells. These potential risks may
 also apply to other agents used in this study.

 6. Participants with any form of systemic immunodeficiency, including acquired deficiency
 such as HIV or primary immunodeficiency such as Severe Combined Immunodeficiency
 Disease, are ineligible. The experimental treatment being evaluated in this protocol
 depends on an intact immune system. Participants who have decreased immune competence
 may be less responsive to the treatment.

 7. Participants on immunosuppressive drugs including corticosteroids.

 8. Participants with autoimmune diseases such as Crohn s disease, ulcerative colitis,
 rheumatoid arthritis, autoimmune hepatitis, autoimmune pancreatitis, or systemic lupus
 erythematosus. Hypothyroidism, vitiligo and other minor autoimmune disorders are not
 exclusionary.

 9. Participants with a second invasive malignancy requiring treatment within the last 2
 years are not eligible with the following exceptions:

 -  Ductal carcinoma in situ (DCIS) of the breast

 -  Cutaneous skin cancers requiring only local excision