The advent of checkpoint blockade immunotherapy has revolutionized the management of metastatic non-small cell lung cancer (NSCLC). Despite the promising evidence for deep and durable responses with these agents the majority of patients fail to respond. The investigators hypothesize that a novel strategy combining radiotherapy and intralesional interleukin-2 (IL-2), a signaling molecule and member of the cytokine family involved in the activation of leukocytes and lymphocytes, may overcome resistance to checkpoint blockade therapy and offer significant clinical benefit to patients who fail to respond to checkpoint blockade alone. The investigators propose a microtrial testing the feasibility of a bold combinatorial immunotherapy strategy consisting of radiotherapy (RT), intralesional IL-2, and check-point blockade for metastatic non-small cell lung cancer patients who have progressed after checkpoint inhibition. IL-2 can upregulate PD-1 expression and activate T-cells.

The advent of checkpoint blockade immunotherapy has revolutionized the management of metastatic non-small cell lung cancer (NSCLC). Despite the promising evidence for deep and durable responses with these agents the majority of patients fail to respond. The investigators hypothesize that a novel strategy combining radiotherapy and intralesional interleukin-2 (IL-2), a signaling molecule and member of the cytokine family involved in the activation of leukocytes and lymphocytes, may overcome resistance to checkpoint blockade therapy and offer significant clinical benefit to patients who fail to respond to checkpoint blockade alone. The investigators propose a microtrial testing the feasibility of a bold combinatorial immunotherapy strategy consisting of radiotherapy (RT), intralesional IL-2, and check-point blockade for metastatic non-small cell lung cancer patients who have progressed after checkpoint inhibition. IL-2 can upregulate PD-1 expression and activate T-cells. There is data supporting combination therapies with IL-2 and checkpoint blockade, IL-2 and radiotherapy, and checkpoint blockade and radiotherapy but clinical data is limited and the triple combination has never been tested. IL-2 + checkpoint blockade was recently tested in a small clinical trial and showed promising results but RT was not included in this trial. As outlined above RT has been demonstrated to increase the efficacy of both IL-2 and checkpoint blockade. The investigators believe that the triple combination of radiotherapy + IL-2 + checkpoint inhibition will be highly effective as RT + IL-2 can serve highly activate the immune system and checkpoint blockade can reverse the immune suppressive pathways induced by tumor and therapy. The investigators hypothesize that the combination of intralesional IL-2 with radiotherapy will act as an "in-situ" vaccine inducing an anti-tumor immune response. The investigators further hypothesize that this vaccine effect will convert patients with primary or secondary resistance to checkpoint blockade into responders since one mechanism of resistance to checkpoint blockade appears to be lack of a pre-existing anti-tumor immune response. The primary endpoint is tolerability, safety and toxicity. Exploratory endpoints include abscopal response rate, objective response rate, disease control rate, progression free survival, and correlative studies. This trial will incorporate robust correlative assays to provide insights into mechanisms of resistance to checkpoint blockade and how this therapy may overcome that resistance. This trial, although small, has the potential to drastically advance both our understanding and treatment of metastatic lung cancer.

This is a pilot phase I study that will evaluate the safety and toxicity of this combinatorial approach. Eligible patients with NSCLC who fail to respond to PD1/PDL1 checkpoint blockade will be enrolled. Patients will continue on checkpoint blockade and receive intralesional IL-2 in combination with hypofractionated radiotherapy. Radiotherapy will be delivered to the treatment lesion during the first week of therapy using an 8 Gy x 3 fractions palliative regimen. Fractions may be delivered on consecutive or every other day but must be completed during week 1 and will not be repeated in future cycles. Immune checkpoint blockade will be started on week 1 day 1, concurrent with radiotherapy and continue with cycles every 2 (nivolumab) or 3 (pembrolizumab) weeks. A total of four Interleukin-2 treatments will be delivered into the treatment lesion by intralesional injections twice weekly starting 24-72 hours after the completion of radiotherapy and to be completed no later than study Day 21. Intralesional injections will be performed by palpation of the lesion or under ultrasound or CT guidance as indicated. Intralesional IL-2 injections will follow guidelines, which we have previously published. Briefly, each patient will receive an initial test dose of 3 x 106 IU of IL-2, which will be escalated to 7 x 106 for the second treatment and then 15 x 106 IU for the final two treatments as tolerated. If a dose level is not tolerated the treatment will be de-escalated to previous dose levels for subsequent treatments. If 3 million IU IL-2 is not tolerated the dose can be de-escalated to 1 million IU IL-2. If 1 million IU IL-2 is not tolerated the treatment will be deemed intolerable and patient removed from study.

Inclusion Criteria:

1. Adults ≥18 years of age with histologically proven NSCLC.

2. Failure to respond to standard of care checkpoint blockade therapy or previously responding patients who progress on checkpoint blockade therapy.

3. ECOG (Eastern Cooperative Oncology Group) performance status score of 0 - 2 (Appendix 1)

4. Presence of a candidate treatment lesion (subcutaneous or nodal lesions are preferable but visceral lesions will be considered) accessible and safe for radiotherapy and serial intralesional injections.

5. Presence of at least one target lesion (distinct from treatment lesion and outside of treatment lesion radiation field) evaluable for response by RECIST 1.1

6. Life expectancy ≥ 6 months

7. The following laboratory results obtained within 14 days of the first study treatment:

   • ANC > 1500 cells/ul
   • WBC count > 2500/uL
   • Lymphocyte count >500/uL
   • Platelet count > 100,000/uL
   • Hemoglobin > 9 g/dL

8. Liver function tests meeting one of the following criteria:

   • AST and ALT < 2.5 x ULN with alkaline phosphatase < 2.5 x ULN OR
   • AST and ALT < 1.5 x ULN, with alkaline phosphatase > 2.5 x ULN

9. Serum bilirubin ≤ 1.0 x ULN.

10. INR and aPTT ≤ 1.5 x ULN.

11. Creatinine clearance > 30 mL/min by Cockcroft-Gault formula.

12. No other active malignancy.

13. For female patients of childbearing potential and male patients with partners of childbearing potential agreement (by patient and/or partner) to use highly effective form(s) of contraception (i.e., one that results in a low failure rate [<1% per year] when used consistently and correctly) and to continue its use for 6 months after trial completion.

14. Signed informed consent.

15. Ability to comply with the protocol.

16. Systolic ≥80.

Exclusion Criteria:

1. Uncontrolled concomitant disease.
2. History of severe autoimmune disease.
3. Treatment with systemic immunostimulatory agents within 4 weeks or five half-lives of the drug, whichever is shorter, prior to enrollment (with the exception of checkpoint blockade therapy).
4. Treatment with systemic corticosteroids or other systemic immunosuppressive medications within past 4 weeks or 5 half-lives whichever is shorter.
5. Pregnant and/or lactating women.
6. Patients unable to tolerate checkpoint inhibitor therapy.
7. Grade 3 or 4 non-hematological, treatment-related AEs.