An abscopal response to radiation and ipilimumab in a patient with metastatic non-small cell lung cancer

Abstract

A posteriori evidence suggests that radiotherapy to a targeted tumor can elicit an immune-mediated abscopal (ab-scopus, away from the target) effect in non-targeted tumors, when combined with an anti-cytotoxic T-lymphocyte antigen-4 monoclonal (CTLA-4) antibody. Concurrent radiotherapy and ipilimumab (a human monoclonal anti-CTLA-4 antibody) induced immune-mediated abscopal effects in poorly immunogenic pre-clinical tumor models and metastatic melanoma patients. However, no such reports exist for patients with metastatic lung adenocarcinoma. We report the first abscopal response in a treatment-refractory lung cancer patient treated with radiotherapy and ipilimumab. A post-treatment increase in tumor-infiltrating cytotoxic lymphocytes, tumor regression, and normalization of tumor markers was observed. One year after treatment with concurrent radiotherapy and ipilimumab the patient is without evidence of disease.

Figures

Figure 1. Registration of PET/CT and CT/simulation to target intrahepatic lesion

The PET/CT from August 2012 (left panels) was imported into the Eclipse planning software (Varian Medical Systems, Inc., Palo Alto, California) and registered to the CT/simulation (right panels) that was acquired prior to treatment. Select axial (top panels), coronal (middle panels), and sagittal (bottom panels) images are displayed. The most hypermetabolic liver lesion was selected as the GTV (white arrows, left panels). The treatment plan was designed with 6-MV photons by means of a coplanar 5-field intensity-modulated technique to encompass the GTV with a 1 cm margin (right panels). The treatment was prescribed to the 100% isodose line to a total dose of 30 Gy distributed over 5 fractions. The isodose lines represent total doses of 30 Gy (yellow), 15 Gy (orange), and 9 Gy (light blue) (right panels).

Figure 2. Ipilimumab and local RT result in an abscopal response

PET imaging and select fused PET/CT axial images from August 2012 (left panels) and January 2013 (right panels) are displayed. The axial images in the second row demonstrate the hypermetabolic liver lesion that was targeted and responded to RT (white arrows, second row). An abscopal response was seen in a left lower lobe lung lesion (white arrows, third row) and a left sacral lesion (white arrows, bottom row). A mixed response was seen in the hilar/mediastinal lymph nodes (striped arrows, third row).

Figure 3. Treatment timeline and the absolute peripheral blood cell counts

A detailed clinical timeline is displayed (A, top panel). A PET/CT on June 8, 2012 demonstrated disease progression prompting a change in the patient's chemotherapy regimen. On June 15, 2012, the patient was started on a chemotherapy regimen containing gemcitabine and vinorelbine. The green marker demarcates the treatment timeline for gemcitabine and vinorelbine (A, top panel). A repeat PET/CT on August 6, 2012, demonstrated continued disease progression. From August 22, 2012 to August 31, 2012 the patient was treated with concurrent RT and ipilimumab. Afterward, he received 3 additional cycles of ipilimumab alone. The blue marker demarcates the treatment timeline for RT and ipilimumab (A [top panel] and B) and data plotted to the right of the vertical dashed line in each graph represents post initiation of RT and ipilimumab treatment (A [bottom 3 panels] and B). The final dose of ipilimumab was given on October 26, 2012. Imaging on November 8, 2012 (CT of the chest abdomen and pelvis) and January 17, 2013 (PET/CT) demonstrated significant treatment responses. During the course of treatment, the patient had serial blood draws. The results of the peripheral absolute blood cell counts (white blood cells [WBCs], ALCs, and AECs) are displayed as number of cells [×103] per μL of whole blood (A, bottom 3 panels), in accordance with the aforementioned treatment timeline (A, top panel). A dramatic drop in CEA levels (a non-specific tumor marker) was observed after treatment with RT and ipilimumab (B). The marker peaked at 119.6 ng/ml (normal levels 0-5 ng/ml) on September 7, 2012, demonstrated a dramatic drop to 5.8 ng/ml on October 26, 2012, and thereafter was maintained at normal levels.

Figure 4. Enhanced tumor-infiltrating lymphocytes in an abscopal lesion

A treatment-naive left supraclavicular nodal metastasis was excised in 2010 and an adjacent non-irradiated nodal metastasis was excised in 2013 (post-treatment with ipilimumab and local RT). The immunologic characteristics of the two specimens were compared (A). An H&E stain demonstrated lymphocytic infiltration largely confined to perivascular areas in the 2010 biopsy specimen (A, top left panel–black arrow), whereas lymphocytes-infiltrated tumor cell nests in the 2013 biopsy specimen (A, top right panel–white arrow). Rare CD8+ cells were present in the 2010 specimen (A, middle left panel). However, a marked increase in CD8+ and TIA+ (a marker for cytotoxic granules) cells was present in the 2013 specimen (A, middle right panel). The inset demonstrates TIA-1+ cells directly interacting with tumor cells (A, bottom right panel). Cells were counted in 10 randomly selected high power fields (HPFs) (B). CD8+ cells were significantly increased (p<0.0001) in the biopsy from 2013. FoxP3+ cells also increased (p<0.05), but the ratio of CD8+/FoxP3+ cells was higher in the 2013 specimen.

Figure 5. PET image one year after treatment with concurrent radiotherapy and ipilimumab

A PET/CT was completed September 2013, one year after treatment with concurrent radiotherapy and ipilimumab. The PET image is displayed and demonstrates no evidence of disease.