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.