Personalized Ultrafractionated Stereotactic Adaptive Radiotherapy (PULSAR) in Preclinical Models Enhances Single-Agent Immune Checkpoint Blockade.

Abstract

PURPOSE:

Harnessing the immune-stimulatory effects of radiation by combining it with immunotherapy is a promising new treatment strategy. However, more studies characterizing immunotherapy and radiation dose scheduling for the optimal therapeutic effect is essential for designing clinical trials.

METHODS AND MATERIALS:

A new ablative radiation dosing scheme, personalized ultrafractionated stereotactic adaptive radiation therapy (PULSAR), was tested in combination with α-PD-L1 therapy in immune-activated and resistant syngeneic immunocompetent mouse models of cancer. Specifically, tumor growth curves comparing immunotherapy and radiation therapy dose sequencing were evaluated in immunologically cold and hot tumor models. The response relative to cytotoxic killer T cells was evaluated using an α-CD8 depleting antibody, and immunologic memory was tested by tumor rechallenge of cured mice.

RESULTS:

We report that both radiation and immunotherapy sequencing, as well as radiation therapy fraction spacing, affect the combination treatment response. Better tumor control was achieved by giving α-PD-L1 therapy during or after radiation, and spacing fractions 10 days apart (PULSAR) achieved better tumor control than traditional daily fractions. We showed that CD8+ depleting antibody abrogated tumor control in the PULSAR combination treatment, and certain treatment schedules induced immunologic memory.

CONCLUSIONS:

These results illustrate that radiation therapy dosing and scheduling affect tumor control, in combination with checkpoint blockade therapies. PULSAR-style radiation dosing is more complementary in combination with single-agent immunotherapy than traditional daily fractions in this preclinical model. Preclinical investigation could prove helpful in designing clinical trials investigating combination therapy.

• Authors: Casey Moore, Ching-Cheng Hsu, Wei-Min Chen, Benjamin P C Chen, Chuanhui Han, Michael Story, Todd Aguilera, Laurentiu M Pop, Raquibul Hannan, Yang-Xin Fu, Debabrata Saha, Robert Timmerman
• Journal: International journal of radiation oncology, biology, physics (Int J Radiat Oncol Biol Phys) Vol. 110 Issue 5 Pg. 1306-1316 (08 01 2021) ISSN: 1879-355X [Electronic] United States
• PMID: 33794306 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 Elsevier Inc. All rights reserved.

Chemical References

• B7-H1 Antigen
• CD274 protein, human
• Immune Checkpoint Inhibitors

Topics

• Animals
• B7-H1 Antigen
• Carcinoma, Lewis Lung (immunology, therapy)
• Cell Line, Tumor
• Colonic Neoplasms (immunology, therapy)
• Dose Fractionation, Radiation
• Female
• Immune Checkpoint Inhibitors (pharmacology)
• Immunologic Memory
• Mice
• Mice, Inbred C57BL
• Precision Medicine (methods)
• Radioimmunotherapy (methods)
• Radiosurgery (methods)
• Radiotherapy Dosage
• Random Allocation
• T-Lymphocytes, Cytotoxic
• Treatment Outcome