Lesion-Level Response Dynamics to Programmed Cell Death Protein (PD-1) Blockade
Juan C Osorio1, Kathryn C Arbour1,2, Dung T Le3
1Memorial Sloan Kettering Cancer Center, New York, NY.
Purpose:
Response to programmed cell death protein 1 (PD-1) blockade is often conceptualized as resulting from reinvigoration of tumor-infiltrating lymphocytes. However, recruited antitumor immunity from the periphery may also be an important contributor to response. A detailed assessment of the response dynamics of individual metastasis could provide insight to the systemic and local features that mediate response and resistance to immunotherapy.
Materials And Methods:
Patients with metastatic non-small-cell lung cancer (NSCLC) or mismatch repair deficiency (MMRD) carcinoma treated with PD-1 monotherapy were evaluated independently. Absolute and percent change of each target lesion were quantified at each computed tomography scan using RECIST. Patterns of progression were predefined as systemic or mixed and were correlated with clinical outcomes.
Results:
A total of 761 individual lesions from 214 patients with NSCLC and 290 lesions from 78 patients with MMRD carcinoma were examined. Individual target lesion responses aligned with best overall response of each patient (85% NSCLC and 93% MMRD lesions responded in patients with partial response/complete response). In responding patients, timing of response was uniform (73% NSCLC and 76% MMRD lesions responded synchronously), and deeper responses were associated with prolonged progression-free survival and overall survival. By contrast, at progression, mixed progression was common (45% of NSCLC and 53% of MMRD) and associated with improved survival compared with those who experienced systemic progression (NSCLC hazard ratio [HR], 0.58; P = .001; MMRD HR, 0.40; P = .07). Organ sites had differential responses, with lymph node and liver metastasis among the most and least responsive, respectively.
Conclusion:
Temporal-spatial patterns of response across individual metastases tend to be uniform, favoring the role of peripheral, clonally directed antitumor immunity as a key mediator of response to PD-1 blockade. In contrast, progression is more heterogeneous, potentially revealing the clinical importance of local features and intertumoral heterogeneity.
Insights
Immune checkpoint inhibitor therapy, specifically programmed cell death protein 1 (PD-1) blockade, shows uniform response across metastases, suggesting peripheral immunity is key. Progression patterns reveal heterogeneity, highlighting local factors in immunotherapy resistance.
Area of Science:
- Immunology
- Oncology
- Medical Imaging
Background:
- Programmed cell death protein 1 (PD-1) blockade response is often attributed to reinvigorated tumor-infiltrating lymphocytes.
- Recruited antitumor immunity from the periphery may also significantly contribute to treatment response.
- Assessing individual metastasis response dynamics can elucidate systemic and local factors in immunotherapy response and resistance.
Purpose of the Study:
- To evaluate the response dynamics of individual metastases in patients receiving PD-1 monotherapy.
- To investigate the role of peripheral immunity versus local tumor factors in response to PD-1 blockade.
- To correlate metastasis response patterns with clinical outcomes in non-small-cell lung cancer (NSCLC) and mismatch repair deficiency (MMRD) carcinoma.
Main Methods:
- Retrospective analysis of patients with metastatic NSCLC or MMRD carcinoma treated with PD-1 monotherapy.
- Quantification of absolute and percent change of target lesions using RECIST criteria at serial CT scans.
- Classification of progression patterns as systemic or mixed, and correlation with progression-free and overall survival.
Main Results:
- Individual lesion responses aligned with overall patient response (85% NSCLC, 93% MMRD).
- Responding lesions showed synchronous response (73% NSCLC, 76% MMRD), with deeper responses correlating to improved survival.
- Mixed progression was common (45% NSCLC, 53% MMRD) and associated with improved survival compared to systemic progression.
Conclusions:
- Uniform temporal-spatial response patterns across metastases suggest a significant role for peripheral, clonally directed antitumor immunity in PD-1 blockade response.
- Heterogeneous progression patterns indicate the clinical importance of local tumor features and intertumoral heterogeneity in immunotherapy resistance.
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