T Cell Receptor Immunotherapy for Patients With Metastatic Non-Small Cell Lung Cancer

Background:

- Patients with metastatic non-small cell lung cancer (NSCLC) have few approved
therapeutic options and those that exist are of transient benefit.

- Recent clinical experiences with experimental agents that release checkpoints on the
host immune response (such as anti-PD-1 and anti-PDL1 antibody) have induced tumor
regressions in patients with NSCLC.

- Data from sequencing the genomes of human cancers have shown that, like malignant
melanoma, NSCLC has a very high rate of tumor-specific genomic mutation.

- In metastatic melanoma, a tumor infiltrating lymphocyte cell therapy product (TIL) can
mediate the regression of bulky disease at any site when administered to an autologous
patient with high dose aldesleukin following a non-myeloablative but lymphodepleting
chemotherapy preparative regimen.

- Recent studies on tumor infiltrating lymphocytes from melanoma have demonstrated that
they can frequently recognize tumor-specific mutated proteins as foreign antigens and
that is one hypothesis as to why melanoma is such an immunogenic tumor.

- We propose to investigate the feasibility, safety, and efficacy of growing and
administering an autologous tumor infiltrating lymphocyte product (TIL) to patients with
metastatic NSCLC.

Objectives:

Primary objective:

-To determine the rate of tumor regression in patients with advanced non-small cell lung
cancer (NSCLC) who receive an autologous tumor infiltrating lymphocyte product (TIL) plus
aldesleukin following a lymphodepleting preparative regimen.

Eligibility:

- Patients who are 18 years of age or older must have:

- Advanced NSCLC refractory to standard therapy

- A site of tumor that can be excised with minimal morbidity and mortality or that
requires excision for clinical indications

- At least one remaining site of measurable disease

- Normal basic laboratory values.

- Patients may not have:

- Concurrent major medical illnesses that preclude aldesleukin administration or
immunosuppression;

- Severe hepatic function impairment due to liver metastatic burden;

- Any form of immunodeficiency;

- Severe hypersensitivity to any of the agents used in this study;

- Symptomatic brain metastases or more than 3 CNS metastases

Design:

- Patients will undergo biopsy or resection to obtain tumor for generation of autologous
tumor infiltrating lymphocyte cultures and autologous cancer cell lines.

- The TIL product will be generated according to current TIL-lab standard operating
procedures, using interleukin-2 and OKT3 antibody.

- All patients will receive a non-myeloablative lymphocyte depleting preparative regimen
of cyclophosphamide and fludarabine

- Cohort 1 will receive TIL on day 0 and then begin high-dose aldesleukin (720,000 IU/kg
IV); cohort 2 will receive TIL on day 0 and then begin low-dose aldesleukin (72,000
IU/kg IV). Assignment to this cohort will be made if there are concomitant medical
conditions that would preclude the use of high-dose aldesleukin

- Clinical and immunologic response will be evaluated about 4-6 weeks after TIL infusion.

- For both cohorts 1 and 2, using a Phase II design, 21 patients will be initially
enrolled in each group to assess toxicity and tumor responses. If two or more of the
first 21 patients per group shows a clinical response (PR or CR), accrual will continue
to 41 patients, targeting a 20% goal for objective response. In order to allow for a
small number of non evaluable patients, a total of 85 patients may be enrolled over 5
years.

- INCLUSION CRITERIA:

1. Measurable metastatic (stage IV) or unresectable non-small cell lung cancer
(including but not limited to squamous cell carcinoma, adenosquamous carcinoma,
or adenocarcinomas) with at least one lesion that is resectable for TIL
generation. (Note: neuroendocrine tumors are not eligible.)

2. Patients with 3 or fewer brain metastases that are less than 1 cm in diameter and
asymptomatic are eligible. Lesions that have been treated with stereotactic
radiosurgery must be clinically stable for 1 month after treatment for the
patient to be eligible. Patients with surgically resected brain metastases are
eligible.

3. All patients must have had at least one appropriate first line systemic therapy
and progressed.

4. Clinical performance status of ECOG 0 or 1.

5. Greater than or equal to 18 years of age and less than or equal to 70 years of
age.

6. Patients of both genders must be willing to practice birth control from the time
of enrollment on this study and for four months after treatment.

7. Willing to sign a durable power of attorney

8. Able to understand and sign the Informed Consent Document

I. Hematology:

- Absolute neutrophil count greater than 1000/mm3 without support of filgrastim

- Normal WBC (> 3000/mm3).

- Hemoglobin greater than 8.0 g/dl. Subjects may be transfused to reach this cut-off.

- Platelet count greater than 100,000/mm3

j. 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 may be less responsive to the experimental
treatment and more susceptible to its toxicities.)

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

k. Chemistry:

- Serum ALT/AST less than 2.5 times the upper limit of normal.

- Serum creatinine less than or equal to 1.6 mg/dl.

- Total bilirubin less than or equal to 2 mg/dl, except in patients with Gilbert s
Syndrome, who must have a total bilirubin less than or equal to 3 mg/dl.

l.Women of child-bearing potential must have a negative pregnancy test because of the

potentially dangerous effects of the treatment on the fetus.

m. More than four weeks must have elapsed since any prior systemic therapy at the time the
patient receives the preparative regimen, and patients toxicities must have recovered to a
grade 1 or less. Patients may have undergone minor surgical procedures or local
radiotherapy within the past 4 weeks.

n. More than two weeks must have elapsed since any prior palliation for major bronchial
occlusion or bleeding at the time the patient receives the preparative regimen, and patient
s toxicities must have recovered to a grade 1 or less.

o. Subjects must be co-enrolled in protocol 03-C-0277

EXCLUSION CRITERIA:

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

2. Ongoing need for pharmacological immunosuppression, including steroids

3. Active systemic infections (e.g.: requiring anti-infective treatment), coagulation
disorders or any other active or uncompensated major medical illnesses.

4. Major bronchial occlusion or bleeding not amenable to palliation.

5. Any form of primary immunodeficiency (such as Severe Combined Immunodeficiency

Disease and AIDS).

6. Concurrent opportunistic infections (The experimental treatment being evaluated in
this protocol depends on an intact immune system. Patients who have decreased immune
competence may be less responsive to the experimental treatment and more susceptible
to its toxicities.)

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

8. Any patient known to have an LVEF less than or equal to 45%.

9. Documented LVEF of less than or equal to 45% tested in patients with:

-Clinically significant atrial and/or ventricular arrhythmias including but not
limited to:

atrial fibrillation, ventricular tachycardia, second or third degree heart block or
have a history of ischemic heart disease, chest pain

-Age greater than or equal to 65 years old

10. Documented FEV1 of less than or equal to 50% predicted in patients with clinical

symptomatology.

11. Any of the following will exclude patients from the high-dose aldesleukin arm, but may
be eligible for the low-dose aldesleukin arm:

- Greater than 2 invasive thoracic procedures

- Poor exercise tolerance

- Greater than 66 years of age

12. Clinically significant patient history which in the judgment of the Principal
Investigator would compromise the patient s ability to tolerate high-dose.

13. Patients who are receiving any other investigational agents.