HERV-E TCR Transduced Autologous T Cells in People With Metastatic Clear Cell Renal Cell Carcinoma

Metastatic renal cell carcinoma (RCC) is an incurable condition. Current therapy for this
disease consists of the serial administration of agents such as VEGF, mTOR inhibitors and
immunotherapy (high-dose (HD) IL-2 or immune-checkpoint inhibitors). Long-term survival can
be achieved with high-doses IL-2 or immune-checkpoint inhibitors. However, of those patients
treated with immunotherapy, three quarters will not respond at all and only 5-8% will achieve
a complete and durable response.

Our team isolated a tumor-specific cytotoxic T lymphocyte (CTL) line from peripheral blood
mononuclear cells (PBMCs) obtained after an allogeneic transplant from a patient who showed
prolonged tumor regression. Using limiting dilution cloning, we identified an allogeneic
(derived from the stem cell donor) CD8+ T-cell clone that killed ccRCC cells in an HLA A11
restricted fashion. Using cDNA expression cloning, we identified a HERV-E derived antigen
expressed in the patient s ccRCC cells to be the target of this T-cell clone. Remarkably, we
found this HERV-E was expressed in the majority of ccRCC cells with no expression in normal
tissues. Based on the identification of the antigenicity of the HERV-E transcripts in ccRCC,
our team in collaboration with Dr. Nishimura s laboratory (Loyola University Cardinal
Bernardin Cancer Center) has cloned, expressed and characterized the TCR from this CD8+
T-cell clone that recognizes an HLA A11 restricted HERV-E antigen.

This research protocol is therefore designed to evaluate the safety and effectiveness of
infusion of HERV-E TCR transduced CD8+/CD34+ enriched T cells in HLA-A*11:01 positive
patients with metastatic clear cell RCC. Subjects will receive a novel non-myeloablative
immunosuppressive conditioning regimen of cyclophosphamide and fludarabine followed by an
infusion of HERV-E TCR transduced CD8+/CD34+ enriched T cells. To mediate T cell survival and
sustain function, moderate-doses of IL-2 (aldesleukin) will be administered intravenously
twice a day for 14 doses.

The primary endpoint is safety by day 21. Secondary endpoints will include overall response
rate, progressionfree survival and overall survival. We will also evaluate for the
persistence of circulating HERV-E TCR transduced CD8+/CD34+ enriched T cells, changes in
immune cell subsets and activation status of T cells, as well as, other immunologic
determinants with clinical outcomes at baseline, at different time points during treatment
and at the time of disease progression.

- INCLUSION CRITERIA:

- Patients must have histologically confirmed RCC with clear-cell component by the
Laboratory of Pathology of 43T the NIH prior to entering this study.

- Patients must be HLA-A 11:01 positive (confirmed by HLA typing at the NIH DTM)

- Patients must have measurable disease and have disease progression during or after the
last treatment regimen and within 6 months before study enrollment

- Patients must have received at least one antiangiogenic drug and an immune-checkpoint
inhibitor (i.e. nivolumab) unless the patient has contraindications to receiving these
medications, the agents are not available to the patient, or the patient declines to
receive these drugs due to personal preference.

- Patients must agree to use adequate contraception (hormonal or barrier method of birth
control; abstinence) prior to study entry, the duration of study participation and 180
days (female patients) or 90 days (male patients) after the end of the treatment if
sexually active and able to bear or beget children. In addition, male patients must
refrain from sperm donation for 90 days after the final dose of investigational
product. Female patients must refrain from egg cell donation for 180 days after the
final dose of investigational product

- Patients must be between the ages of 18 and 70 years.

- Patient must have an anticipated life expectancy of at least 3 months.

- Patients must have a performance status of 0 or 1 ECOG performance status (PS) scale.

- Patients must have a caregiver willing to stay with them during the first month of
treatment (30 days +/- 7 days).

- Patients receiving treatment with bisphosphonates or denosumab are eligible for
enrollment if on a stable dose for greater than or equal to 4 weeks

- Serology:

- Seronegative for HIV antibody. (The experimental treatment being evaluated in
this protocol depends on an intact immune system. Patients who are HIV
seropositive can have decreased immune-competence and thus be less responsive to
the experimental treatment and more susceptible to its toxicities.)

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

- Organ Function

- Hematology

- Absolute neutrophil count greater than or equal to 1000/ microL

- WBC greater than or equal to 3000/microL

- Platelet count greater than or equal to 100.000/microL (without transfusional
support)

- Hemoglobin greater than or equal to 8gr/dl (without transfusional support)

- Chemistry

- Serum AST/ALT less than or equal to 2.5 x upper limit of normal (ULN)

- Total bilirubin less than or equal to 1.5 mg/dl except for patients with Gilbert
s syndrome who must have a total bilirubin less than or equal to 3 mg/dl

- Calculated creatinine clearance by the method of CKI-EPI greater than or equal to
50 ml/min/1.73m2

- INR < 1.5

- Cardiology

- Estimated left ventricular ejection fraction by echocardiography greater than or
equal to 45%

- Respiratory

- Predicted DLCO / Alveolar Volume Adjusted by PFT > 45%

- Patients must have the ability to provide written informed consent prior to study
specific screening procedures, with the understanding that the patient has the right
to withdraw from the study at any time.

EXCLUSION CRITERIA:

- Patients that require immediate therapy due to tumor mass effects or spinal cord
compression.

- Patients must not have had standard of care anti-VEGFR therapy (mean half-life around
30 hours), mTOR inhibitors (mean half-life around 30 hours), radiotherapy, or major
surgery within the last 2 weeks prior to T-cell infusion. For PD-1/PD-L1 inhibitors or
CTLA-4 inhibitors, a 4-week period must have elapsed before T-cell infusion. For
recent experimental therapies a 28-day period must have elapsed before infusing
expanded T-cells.

- Patients with active CNS involvement by malignancy either by imaging or cerebrospinal
fluid involvement or biopsy-proven (due to poor prognosis and potential for
neurological dysfunction that would confound evaluation of neurological and other
adverse events) except for:

1. Patients with single brain metastases of <1cm treated with either stereotactic or
gamma knife radiotherapy and remained stable on MRI for 2 weeks are eligible.

2. Patients with 3 or fewer brain metastases of <1cm treated with either
stereotactic or gamma knife radiotherapy and remained stable on MRI for 4 weeks
are eligible.

3. Patients with surgically resected brain metastases and no evidence of active
disease in the CNS at the time of screening evaluation are eligible.

4. These patients may be enrolled at the discretion of the Principal Investigator

- Patients with hypercalcemia (>10 mg/dL) of malignancy.

- Patients with hypercalcemia (>2.5 mmol/L) of malignancy.

-Any prior Grade greater than or equal to 3 immune-related adverse event (irAE) while
receiving immunotherapy, including anti-

CTLA4 treatment, or any unresolved irAE > Grade 1. Note: Active or history of vitiligo or
hypothyroidism will not be a basis for exclusion.

- Patients with second malignancies in addition to their clear cell RCC are not eligible
if the second malignancy has required treatment (including maintenance therapy) within
the past 4 years or is not in complete remission. There are exceptions to this
criterion: successfully treated non-metastatic basal cell, squamous cell skin
carcinoma, in situ non-invasive cervical cancer and in situ non-invasive breast
cancer.

- Women of child-bearing potential who are pregnant or breastfeeding because of the
potentially dangerous effects of the preparative chemotherapy on the fetus or infant.

- Active uncontrolled systemic infections (defined as infections causing fevers and/or
infections requiring intravenous antibiotics when intravenous antibiotics have been
administered for less than 72 hours).

- Active coagulation disorders or other major uncontrolled medical illnesses of the
respiratory, endocrine, renal, gastrointestinal, genitourinary or immune system,
active obstructive or restrictive pulmonary disease, active autoimmune diseases such
as rheumatoid arthritis.

- Patients who have recent history of cerebrovascular accident, transient ischemic
attack should be cleared by the neurology consult service before enrolling this study.

- Patients who have recent history of coronary artery disease or cardiac arrhythmia
should be cleared by the cardiology consult service before enrolling this study.

- Any form of primary immunodeficiency (such as Severe Combined Immunodeficiency
Disease).

- Patients with autoimmune diseases such as Crohn s disease, ulcerative colitis,
rheumatoid arthritis, autoimmune hepatitis or pancreatitis, and systemic lupus
erythematosus that requires treatment with chronic immunosuppressive therapy.

- Systemic corticosteroid steroid therapy of any dose is not allowed within 14 days
prior to the required leukapheresis, or the initiation of the conditioning
chemotherapy regimen. The following are exceptions to this criterion:

- Intranasal, inhaled, and topical steroids

- Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of
prednisone or equivalent

- Steroids as premedication for hypersensitivity reactions (e.g., CT scan
premedication).

In the case of short-term use of systemic corticosteroids (less than 24 hours within 28
days) of greater than 10 mg/day of prednisone or an equivalent corticosteroid, the required
washout period prior to starting the leukapheresis is 7 days.

- History of severe immediate hypersensitivity reaction to any of the agents used in
this study.

- Unable to understand the investigational nature of the study or give informed consent
and does not have a legally authorized representative or surrogate that can provide
informed consent.

- Any condition that, in the opinion of the investigator, would interfere with
evaluation of the investigational product or interpretation of subject safety or study
results.