Fractionated Radiation Therapy Stimulates Antitumor Immunity Mediated by Both Resident and Infiltrating Polyclonal T-cell Populations when Combined with PD-1 Blockade

Abstract

Fractionated RT modulates the local TCR repertoire 2 Translational Relevance. Radiotherapy (RT) is well documented to be immunogenic; however, systemic anti-tumor immune responses outside of the irradiated tumor field, termed the "abscopal effect", are rare in patients. The lack of abscopal effect is poorly understood, particularly in the context of low-dose daily fractionated RT, the most common regimen used in clinical practice. We demonstrate that 5 daily fractions of 2 Gy induces a polyclonal T-cell response at the irradiation site which is dominated by the expansion of pre-existing T-cell clones. However, Conclusions:These data provide evidence that RT can enhance T-cell trafficking to locally-treated tumor sites and augment pre-existing anti-cancer T-cell responses with the capacity to mediate regression of out-of-field tumor lesions when delivered in combination with αPD-1 mAb therapy.

The Course of Immune Stimulation by Photodynamic Therapy: Bridging Fundamentals of Photochemically Induced Immunogenic Cell Death to the Enrichment of T‐Cell Repertoire

“…Administration of anti‐PD1 or anti‐CTLA4 antibodies presumably helps to stabilize the PDT‐induced, highly diverse and clonally expanded, activated T cells, resulting in a more robust antitumor immunity as reported in several PDT studies listed in Table . The concept of T‐cell repertoire enrichment has been reported for radiotherapy , and as such, we propose that PDT can also play a similar role in expanding the number of activated TSA‐specific clonotypes for a more substantive and comprehensive attack on PDT‐treated tumors. Examining the T‐cell repertoire diversity status before and after PDT treatment could, therefore, be a valuable parameter to evaluate outcomes of PDT combination therapies.…”

Immune checkpoint inhibitors in advanced nasopharyngeal carcinoma: Beyond an era of chemoradiation?

“…There is also currently no consistent cut‐off value between studies for determining positivity for PD‐L1 . Finally, PD‐L1 testing was performed on tissue obtained postchemotherapy for the NCI‐9742 and KEYNOTE‐028 trials, which can overestimate PD‐L1 expression . Although prechemotherapy PD‐L1 expression would be more accurate, this may be unfeasible to achieve.…”

“…CD8 + T cells can then promote tumour specific killing. However, PD‐L1 is upregulated after irradiation and chemotherapy, prompting T‐cell apoptosis and restricting the immune response upon binding with PD1 . The addition of anti‐PD1/PD‐L1 blocks this interaction, facilitating synergistic antitumour immunity (Figs.…”

Rationale and emerging strategies for immune checkpoint blockade in soft tissue sarcoma

“…Decreased rates of metastasis would significantly improve outcomes for patients with STS. Neoadjuvant radiation therapy is often used to treat sarcoma and reportedly has contributed to an antitumor immune response with immune checkpoint blockade in many preclinical and clinical studies with various tumor types . To date, no clinical studies combining radiation therapy with immunotherapy to treat STS have been presented or published, but ongoing work is reviewed below.…”

“…Neoadjuvant radiation therapy is often used to treat sarcoma and reportedly has contributed to an antitumor immune response with immune checkpoint blockade in many preclinical and clinical studies with various tumor types. 34,37,61,62 To date, no clinical studies combining radiation therapy with immunotherapy to treat STS have been presented or published, but ongoing work is reviewed below. NEXIS (NCT03116529) is a single-arm study in which 35 patients with intermediate-grade or high-grade STS >5 cm in the trunk (nonretroperitoneal) or extremity receive neoadjuvant and adjuvant durvalumab and neoadjuvant tremelimumab with preoperative radiation therapy (at least 50 Gy at 1.8-2 Gy per fraction).…”