Durable cancer regression off-treatment and effective reinduction therapy with an anti-PD-1 antibody

Abstract

Purpose: Results from the first-in-human phase I trial of the anti-programmed death-1 (PD-1) antibody BMS-936558 in patients with treatment-refractory solid tumors, including safety, tolerability, pharmacodynamics, and immunologic correlates, have been previously reported. Here, we provide long-term follow-up on three patients from that trial who sustained objective tumor regressions off therapy, and test the hypothesis that reinduction therapy for late tumor recurrence can be effective.

Experimental design: Three patients with colorectal cancer, renal cell cancer, and melanoma achieved objective responses on an intermittent dosing regimen of BMS-936558. Following cessation of therapy, patients were followed for more than 3 years. A patient with melanoma who experienced a prolonged partial regression followed by tumor recurrence received reinduction therapy.

Results: A patient with colorectal cancer experienced a complete response, which is ongoing after 3 years. A patient with renal cell cancer experienced a partial response lasting 3 years off therapy, which converted to a complete response, which is ongoing at 12 months. A patient with melanoma achieved a partial response that was stable for 16 months off therapy; recurrent disease was successfully treated with reinduction anti-PD-1 therapy.

Conclusion: These data represent the most prolonged observation to date of patients with solid tumors responding to anti-PD-1 immunotherapy and the first report of successful reinduction therapy following delayed tumor progression. They underscore the potential for immune checkpoint blockade with anti-PD-1 to reset the equilibrium between tumor and the host immune system.

Figure 1

Response of metastatic colorectal cancer to anti-PD-1 therapy. (A) Computed tomographic scan showing partial regression of a representative lymph node metastasis in a patient with CRC, after receiving a single dose of anti-PD-1. (B) H&E staining and IHC analysis of primary colon tumor from this patient, showing PD-L1+ lymphohistiocytic infiltrates surrounding tumor cells, and rare PD-L1+ tumor cells, interposed with CD3+, PD-1+ infiltrating T cells. Arrow denotes tumor cells. 200x original magnification.

Figure 1

Response of metastatic colorectal cancer to anti-PD-1 therapy. (A) Computed tomographic scan showing partial regression of a representative lymph node metastasis in a patient with CRC, after receiving a single dose of anti-PD-1. (B) H&E staining and IHC analysis of primary colon tumor from this patient, showing PD-L1+ lymphohistiocytic infiltrates surrounding tumor cells, and rare PD-L1+ tumor cells, interposed with CD3+, PD-1+ infiltrating T cells. Arrow denotes tumor cells. 200x original magnification.

Figure 2

Regression of metastatic RCC following anti-PD-1 therapy, with “immune related” response characteristics. (A) Contrast-enhanced CT scans showing regression of a biopsy-proven paraspinal intramuscular metastasis (top row, arrows) and concomitant progression followed by regression of a pancreatic lesion (bottom row, arrows) in a patient who received 3 doses of anti-PD-1. (B) Newly appearing lesion radiologically compatible with brain metastasis, demonstrated on T1-weighted contrast enhanced magnetic resonance imaging, with intralesional hemorrhage and surrounding edema (left panel). Pathologic evaluation of the resected lesion on H&E staining revealed fibrosis (asterisk), a chronic inflammatory cell infiltrate, and old hemorrhage, consistent with a resolving process. There was no morphologic or immunohistochemical evidence of RCC (no expression of PAX-8, EMA, or AE1/AE3; data not shown). Immunostaining to characterize the inflammatory infiltrate demonstrated a lymphocytic infiltrate with CD8 predominance when compared to CD4. The CD8 cells were also TIA-1 positive, supporting a cytotoxic phenotype (not shown). Staining for CD68 highlighted numerous hemosiderin-laden macrophages in the inflammatory infiltrate. 200x original magnification. (C) Continued regression of multiple metastatic sites over time, following cessation of anti-PD-1 therapy. Drug administration indicated by arrows. The lesion marked with an asterisk became calcified on CT scan and showed no FDG activity on PET scan. LN, lymph node; IM, intramuscular.

Figure 2

Regression of metastatic RCC following anti-PD-1 therapy, with “immune related” response characteristics. (A) Contrast-enhanced CT scans showing regression of a biopsy-proven paraspinal intramuscular metastasis (top row, arrows) and concomitant progression followed by regression of a pancreatic lesion (bottom row, arrows) in a patient who received 3 doses of anti-PD-1. (B) Newly appearing lesion radiologically compatible with brain metastasis, demonstrated on T1-weighted contrast enhanced magnetic resonance imaging, with intralesional hemorrhage and surrounding edema (left panel). Pathologic evaluation of the resected lesion on H&E staining revealed fibrosis (asterisk), a chronic inflammatory cell infiltrate, and old hemorrhage, consistent with a resolving process. There was no morphologic or immunohistochemical evidence of RCC (no expression of PAX-8, EMA, or AE1/AE3; data not shown). Immunostaining to characterize the inflammatory infiltrate demonstrated a lymphocytic infiltrate with CD8 predominance when compared to CD4. The CD8 cells were also TIA-1 positive, supporting a cytotoxic phenotype (not shown). Staining for CD68 highlighted numerous hemosiderin-laden macrophages in the inflammatory infiltrate. 200x original magnification. (C) Continued regression of multiple metastatic sites over time, following cessation of anti-PD-1 therapy. Drug administration indicated by arrows. The lesion marked with an asterisk became calcified on CT scan and showed no FDG activity on PET scan. LN, lymph node; IM, intramuscular.

Figure 2

Regression of metastatic RCC following anti-PD-1 therapy, with “immune related” response characteristics. (A) Contrast-enhanced CT scans showing regression of a biopsy-proven paraspinal intramuscular metastasis (top row, arrows) and concomitant progression followed by regression of a pancreatic lesion (bottom row, arrows) in a patient who received 3 doses of anti-PD-1. (B) Newly appearing lesion radiologically compatible with brain metastasis, demonstrated on T1-weighted contrast enhanced magnetic resonance imaging, with intralesional hemorrhage and surrounding edema (left panel). Pathologic evaluation of the resected lesion on H&E staining revealed fibrosis (asterisk), a chronic inflammatory cell infiltrate, and old hemorrhage, consistent with a resolving process. There was no morphologic or immunohistochemical evidence of RCC (no expression of PAX-8, EMA, or AE1/AE3; data not shown). Immunostaining to characterize the inflammatory infiltrate demonstrated a lymphocytic infiltrate with CD8 predominance when compared to CD4. The CD8 cells were also TIA-1 positive, supporting a cytotoxic phenotype (not shown). Staining for CD68 highlighted numerous hemosiderin-laden macrophages in the inflammatory infiltrate. 200x original magnification. (C) Continued regression of multiple metastatic sites over time, following cessation of anti-PD-1 therapy. Drug administration indicated by arrows. The lesion marked with an asterisk became calcified on CT scan and showed no FDG activity on PET scan. LN, lymph node; IM, intramuscular.

Figure 3

Response of metastatic melanoma to re-induction anti-PD-1 therapy. (A) Initial partial regression of liver and lymph node (LN) metastases in a melanoma patient treated with anti-PD-1. Drug administration indicated by arrows. Recurrent disease in mediastinal lymph nodes while off therapy was successfully treated with re-induction therapy. The lesion marked with an asterisk developed peripheral calcification and demonstrated minimal PET activity. (B) Membranous (cell surface) PD-L1 expression by metastatic melanoma cells in a transbronchial biopsy of a subcarinal lymph node mass, prior to re-induction therapy. Tumor infiltration by CD8+, PD-1+ T cells is evident (arrows). 200x original magnification. (C) PET scans prior to first treatment with anti-PD-1 (August 2007), prior to re-induction therapy (December 2010), and following re-induction (November 2011). Resolution of a left axillary lymph node metastasis that was present prior to anti-PD-1 therapy, and response of a new subcarinal lymph node metastasis to re-induction therapy, are shown (arrows). (D) Regression of new mediastinal lymph node metastasis following re-induction therapy with anti-PD-1, demonstrated in contrast-enhanced CT scans.

Figure 3

Response of metastatic melanoma to re-induction anti-PD-1 therapy. (A) Initial partial regression of liver and lymph node (LN) metastases in a melanoma patient treated with anti-PD-1. Drug administration indicated by arrows. Recurrent disease in mediastinal lymph nodes while off therapy was successfully treated with re-induction therapy. The lesion marked with an asterisk developed peripheral calcification and demonstrated minimal PET activity. (B) Membranous (cell surface) PD-L1 expression by metastatic melanoma cells in a transbronchial biopsy of a subcarinal lymph node mass, prior to re-induction therapy. Tumor infiltration by CD8+, PD-1+ T cells is evident (arrows). 200x original magnification. (C) PET scans prior to first treatment with anti-PD-1 (August 2007), prior to re-induction therapy (December 2010), and following re-induction (November 2011). Resolution of a left axillary lymph node metastasis that was present prior to anti-PD-1 therapy, and response of a new subcarinal lymph node metastasis to re-induction therapy, are shown (arrows). (D) Regression of new mediastinal lymph node metastasis following re-induction therapy with anti-PD-1, demonstrated in contrast-enhanced CT scans.

Figure 3

Response of metastatic melanoma to re-induction anti-PD-1 therapy. (A) Initial partial regression of liver and lymph node (LN) metastases in a melanoma patient treated with anti-PD-1. Drug administration indicated by arrows. Recurrent disease in mediastinal lymph nodes while off therapy was successfully treated with re-induction therapy. The lesion marked with an asterisk developed peripheral calcification and demonstrated minimal PET activity. (B) Membranous (cell surface) PD-L1 expression by metastatic melanoma cells in a transbronchial biopsy of a subcarinal lymph node mass, prior to re-induction therapy. Tumor infiltration by CD8+, PD-1+ T cells is evident (arrows). 200x original magnification. (C) PET scans prior to first treatment with anti-PD-1 (August 2007), prior to re-induction therapy (December 2010), and following re-induction (November 2011). Resolution of a left axillary lymph node metastasis that was present prior to anti-PD-1 therapy, and response of a new subcarinal lymph node metastasis to re-induction therapy, are shown (arrows). (D) Regression of new mediastinal lymph node metastasis following re-induction therapy with anti-PD-1, demonstrated in contrast-enhanced CT scans.

Figure 3

Response of metastatic melanoma to re-induction anti-PD-1 therapy. (A) Initial partial regression of liver and lymph node (LN) metastases in a melanoma patient treated with anti-PD-1. Drug administration indicated by arrows. Recurrent disease in mediastinal lymph nodes while off therapy was successfully treated with re-induction therapy. The lesion marked with an asterisk developed peripheral calcification and demonstrated minimal PET activity. (B) Membranous (cell surface) PD-L1 expression by metastatic melanoma cells in a transbronchial biopsy of a subcarinal lymph node mass, prior to re-induction therapy. Tumor infiltration by CD8+, PD-1+ T cells is evident (arrows). 200x original magnification. (C) PET scans prior to first treatment with anti-PD-1 (August 2007), prior to re-induction therapy (December 2010), and following re-induction (November 2011). Resolution of a left axillary lymph node metastasis that was present prior to anti-PD-1 therapy, and response of a new subcarinal lymph node metastasis to re-induction therapy, are shown (arrows). (D) Regression of new mediastinal lymph node metastasis following re-induction therapy with anti-PD-1, demonstrated in contrast-enhanced CT scans.