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Durable Cancer Regression Off-Treatment and Effective Reinduction Therapy With an Anti-PD-1 Antibody
Clin Cancer Res. 2012 Nov 20;[Epub Ahead of Print], EJ Lipson, WH Sharfman, CG Drake, et al
TAKE-HOME MESSAGE
Patients with treatment-refractory solid tumors who responded to the anti–programmed death-1 (PD-1) antibody BMS-936558 had remarkably durable remissions, including continued tumor regression off therapy and, in a melanoma patient, successful reinduction therapy after delayed progression.
EXPERT COMMENTARY
Lee S. Schwartzberg, MD, FACP
Immunotherapy as a treatment for cancer is one of the oldest systemic modalities, well predating chemotherapy. Our previous rudimentary understanding of the complex immune system, which can either tolerate or reject tumor cells based on a host of conditions, has limited the practical application of immune-based therapy to a few specific examples. This situation is now rapidly changing. Critical immune pathways, such as the programmed death receptor (PD-1) and ligand (PD-1L) interaction, can be manipulated to broadly treat a variety of cancers. A PD-1 antibody has generated great excitement by demonstrating in the clinic that modulation of this pathway can reduce cancer immunosuppression and lead to clinical responses.
We are still at the very beginning of understanding how best to utilize immunotherapy. As the current study in Clinical Cancer Research demonstrates, treatment with anti-PD-1 antibody can lead to prolonged, unmaintained remissions, which are very different than the response to chemotherapy or other biologicals. Moreover, retreatment with the antibody in progressors can be associated with a second prolonged response, suggesting that intrinsic resistance does not develop in all patients after initial pathway alteration. These exciting results remind us that a tremendous amount of clinical research will be required to optimize immunotherapy added to the other aspects of our armamentarium of cancer therapeutics.
SUMMARY
OncologySTAT Editorial Team
The programmed death-1 (PD-1) pathway plays an important role in the down-modulation of anti-tumor immunity. Immune checkpoint blockade with anti-PD-1 therapy has the potential to reverse cancer immunosuppression and “reset” the equilibrium between tumor and the host immune system.
In the first-in-human phase I trial of the anti-PD-1 antibody BMS-936558, 3 of 39 patients with treatment-refractory solid tumors had an objective response to an intermittent dosing regimen. Lipson et al report long-term follow-up of these three patients.
A man with metastatic colorectal cancer had received multiple chemotherapy regimens with only temporary responses. In the current trial, the patient had a partial response to a single dose of anti-PD-1 and received five doses over the next 9 months. He ultimately achieved a complete response (CR), which is ongoing at 3 years off therapy.
Immunohistochemical studies of archived tissue from the patient’s primary tumor 4 years before anti-PD-1 therapy showed cell surface expression of PD-L1 (a PD-1 ligand) by infiltrating macrophages and lymphocytes and by rare tumor cells. This suggests a correlation between tumor cell surface PD-L1 expression and the likelihood of response to anti-PD-1 therapy, but further study is required.
The second patient, with metastatic clear cell renal carcinoma, had disease progression despite numerous systemic therapies. In the current study, the patient had a mixed response to a single dose of anti-PD-1: pulmonary, lymph node, and intramuscular metastases were regressing, but lesions in the pancreas and bone were growing. After two more doses, the patient achieved a partial response (PR). The pancreatic lesion had disappeared and the bone metastasis was slowly resolving. A year later a brain lesion was removed, but showed no evidence of tumor, consistent with a resolved lesion. The metastatic lesions continued to regress off therapy, and 2 years later, a CR was documented. The patient remains in CR more than 4 years after discontinuing anti-PD-1 therapy.
The third patient had metastatic melanoma that progressed despite therapy. In 8 weeks after a single dose of anti-PD-1, the patient had a mixed response, with some lesions regressing and others growing. Two more doses given over the next year also produced a mixed response. After another year of anti-PD-1 therapy, a PR was documented, and therapy was discontinued.
When the melanoma again progressed, biopsy showed intense surface tumor cell expression of PD-L1. The protocol was modified to allow this patient to receive reinduction therapy with anti-PD-1. After two doses, she had a new PR. She continues to receive anti-PD-1 and remains in PR 16 months after reinduction. The successful repeat application of PD-1 blockade in this patient suggests a potential role for “maintenance” immunotherapy, with anti-PD-1 given on an intermittent schedule after an initial response.
The mixed responses seen in the patients with renal cell cancer and melanoma highlight the importance of developing new immune-related RECIST criteria to assess the often unconventional response patterns seen with immune checkpoint blockade.
Recently reported results of a larger phase I trial using biweekly anti-PD-1 showed durable responses in non–small cell lung cancer, melanoma, and renal cell cancer with 1 year or more of follow-up. This trial may help form the basis of future studies combining immunotherapy approaches for synergistic effect.
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