Intratumoral Administration of CCL21-gene Modified Dendritic Cell With Intravenous Pembrolizumab for Advanced NSCLC

A phase I, non-randomized, dose escalating, multi-cohort trial followed by dose expansion at
the dose established during dose escalation (ExD) will be conducted. During dose escalation,
a modified 3+3 design will be used. Three patients will be assigned to each cohort. Patients
enrolled into a given cohort will receive the same Ad-CCL21-DC dose by CT-guided or
bronchoscopic intratumoral injection followed by intravenous pembrolizumab 200mg one hour
after DC injection on days 0, 21, and 42, and intravenous pembrolizumab 200mg every three
weeks thereafter for up to a year. The Ad-CCL21-DC dose is 1 x 107 cells/injection in the
first cohort (1), and will be increased to 3 x 107 cells/injection (2) pending tolerability
in earlier cohort. Dose escalation may proceed only if all 3 patients enrolled in the lower
dose cohort experience no DLT or 1 of 6 patients in a cohort has a DLT. If a patient dies
within 30 days of receiving investigational treatment and the death is considered to be at
least possibly related, further study enrolment will be held until further evaluation by the
UCLA DSCMB. If the dose regimen in cohort 1 (Ad-CCL21-DC 1 x 107 cells/injection) is not well
tolerated, de-escalation to Ad-CCL21-DC 0.5 x 107 cells/injection will be allowed (-1). If
the dose regimen specified for Cohort 2 (Ad-CCL21-DC 3 x 107 cells/injection) is not the
maximum tolerated dose (MTD), no further dose escalation will be conducted, and this dose
level will be defined as maximum administered dose (MAD).

After completion of the dose-escalation phase, all safety and tolerability data will be
reviewed and the ExD will be determined. A dose expansion cohort of 24 patients (D) will be
enrolled and treated at ExD for up to a year. All enrolled patients will continue to be
followed by a physician, and undergo a history and physical examination every 3 months until
progressive disease (PD) or withdrawal from the study. Eligible patients will be assigned to
a cohort and will receive intratumoral injections of autologous Ad-CCL21-DC and intravenous
pembrolizumab in conjunction with tumor sampling and patient monitoring

Inclusion Criteria:

1. Adults over the age of 18 capable of giving informed consent.

2. Stage IV pathologically proven NSCLC.

3. Staining for PD-L1 in less than half of the tumor cells using the CC23 antibody (0%
staining is acceptable)

4. Measurable disease by RECIST Guidelines (see Appendix B).

5. ECOG performance status of 0, 1(see Appendix A).

6. Must be naïve to systemic treatment for NSCLC. Patients who received adjuvant or
neo-adjuvant chemotherapy

7. Adequate renal function (defined as BUN≤40 or serum creatinine≤2).

8. Adequate liver function (defined as serum total bilirubin≤2X the upper limits of
normal (ULN), or serum transaminases≤3X ULN).

9. Adequate coagulation parameters (defined as PT and/or PTT≤1.5X ULN or
platelets≥100,000).

10. Adequate neutrophils (defined as absolute neutrophil count≥1,500/mm3).

11. In woman who have not experienced menopause, negative pregnancy test prior to
initiation of treatment and adequate contraception throughout treatment.

12. All subjects must demonstrate adequate respiratory function (defined as SaO2 >90% on
room air; PCO2 <45mmHg; or FEV1 >1.0 liter).

13. Patients with a major endobronchial lesion in the segmental, lobar, or mainstem
bronchus with complete obstruction of the airway may be eligible for bronchoscopic
injection if there is no evidence of respiratory failure (defined as SaO2 >90% on room
air; PCO2 <45mmHg; or FEV1 >1.0 liter).

14. Patients with an endobronchial lesion in the segmental bronchus with variable stenosis
(not completely obstructed) and not amenable to standard palliative airway treatments
(i.e. laser and stenting) may be eligible for bronchoscopic injection if there is no
evidence of respiratory failure (defined as SaO2 >90% on room air; PCO2 <45mmHg; or
FEV1 >1.0 liter).

15. Subjects with bullous disease may undergo CT-guided transthoracic injection if the
targeted tumor has an intended needle path without crossing bullae.

Exclusion Criteria:

1. Previous systemic therapy for Stage IV NSCLC, including chemotherapy, radiation
therapy or non-cytotoxic investigational agents.

2. Comorbid disease or a medical condition that would impair the ability of the patient
to receive or comply with the study protocol.

3. Any use of systemic corticosteriods within 10 days of treatment or during treatment.

4. Renal insufficiency (defined as BUN>40 or serum creatinine>2).

5. Liver insufficiency (defined as serum total bilirubin > 2x ULN, or serum transaminases
> 3X ULN). Note: Transaminases can be up to 5X ULN in the setting of liver metastases

6. Coagulopathy (defined as PT and/or PTT > 1.5X ULN or platelets < 100,000).

7. Neutropenia (defined as absolute neutrophil count < 1,500/mm3).

8. Respiratory failure (defined as SaO2 <90% on room air; PCO2 >44mmHg; or FEV1 <1.0
liter)

9. Acute viral, bacterial, or fungal infection, which requires specific therapy. Acute
therapy must have been completed within 14 days prior to study treatment.

10. HIV infected patients.

11. Hypersensitivity to any reagents used in the study.

12. Pregnancy or inadequate contraception.

13. Lactating females.

14. Active CNS metastasis, which has not been treated with radiation therapy

15. Subjects with organ allografts.

16. Subjects with bullous disease may not undergo CT-guided transthoracic injection if the
targeted tumor has an intended needle path that requires crossing the bullae.

17. Previous or concurrent evidence of autoimmune disease requiring systemic steroids.

18. Patients with a major endobronchial lesion in the lobar or mainstem bronchus amenable
to standard palliative airway treatments or with >50% stenosis (not completely
obstructed airway) will be excluded from bronchoscopic injection.

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