Potential and unsolved problems of anti-PD-1/PD-L1 therapy combined with radiotherapy

Cao, Yiyi; Li, Wenbo; Wang, Zhengjie; Hua, Peng

doi:10.1177/0300891620940382

Cited by 9 publications

(7 citation statements)

References 90 publications

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“…Several factors need to be considered to maximize the therapeutic effect and minimize the risk of toxicity from the combination of PD‐1/PD‐L1 blockade and radiotherapy. These include the sequence of application (concurrent or sequential), radiation dose and fractions, and safety of the combination treatment 61,62 . While preclinical investigations and some clinical trials have favoured the concurrent application sequence of PD‐1/PD‐L1 blockade and radiotherapy, 55,63,64 other trials have supported the effectiveness of sequential radiotherapy combined with PD‐1/PD‐L1 inhibition 59,60 .…”

Section: Combination Of Pd‐1/pd‐l1 Blockade and Radiotherapymentioning

confidence: 99%

“…These include the sequence of application (concurrent or sequential), radiation dose and fractions, and safety of the combination treatment. 61,62 While preclinical investigations and some clinical trials have favoured the concurrent application sequence of PD-1/PD-L1 blockade and radiotherapy, 55,63,64 other trials have supported the effectiveness of sequential radiotherapy combined with PD-1/ PD-L1 inhibition. 59,60 Moreover, preclinical studies found that radiation delivered as single high dose of 20 Gy could impair tumour immunogenicity, whereas fractionated radiotherapy could stimulate anti-tumour immunity and demonstrated effective abscopal responses when combined with anti-CTLA-4 antibody.…”

Section: Considerations For the Combination Approachmentioning

confidence: 99%

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Improving the synergistic combination of programmed death‐1/programmed death ligand‐1 blockade and radiotherapy by targeting the hypoxic tumour microenvironment

et al. 2022

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Immune checkpoint inhibition with PD-1/PD-L1 blockade is a promising area in the field of anti-cancer therapy. Although clinical data have revealed success of PD-1/PD-L1 blockade as monotherapy or in combination with CTLA-4 or chemotherapy, the combination with radiotherapy could further boost antitumour immunity and enhance clinical outcomes due to the immunostimulatory effects of radiation. However, the synergistic combination of PD-1/PD-L1 blockade and radiotherapy can be challenged by the complex nature of the tumour microenvironment (TME), including the presence of tumour hypoxia. Hypoxia is a major barrier to the effectiveness of both radiotherapy and PD-1/ PD-L1 blockade immunotherapy. Thus, targeting the hypoxic TME is an attractive strategy to enhance the efficacy of the combination. Addition of compounds that directly or indirectly reduce hypoxia, to the combination of PD-1/ PD-L1 inhibitors and radiotherapy may optimize the success of the combination and improve therapeutic outcomes. In this review, we will discuss the synergistic combination of PD-1/PD-L1 blockade and radiotherapy and highlight the role of hypoxic TME in impeding the success of both therapies. In addition, we will address the potential approaches for targeting tumour hypoxia and how exploiting these strategies could benefit the combination of PD-1/PD-L1 blockade and radiotherapy.

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Section: Combination Of Pd‐1/pd‐l1 Blockade and Radiotherapymentioning

confidence: 99%

Section: Considerations For the Combination Approachmentioning

confidence: 99%

Improving the synergistic combination of programmed death‐1/programmed death ligand‐1 blockade and radiotherapy by targeting the hypoxic tumour microenvironment

et al. 2022

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“…Most of the clinical trials do not have a control arm and mix ICI-naïve and ICI-refractory patients. Anti-PD-1 has been administered between 0 to 28 days before RT [ 72 , 73 ]. Unlike anti-CTLA-4 or anti-TGFß, the optimal administration schedule of anti-PD-1/PD-L1 and other checkpoints targeting CD8 + T-cell (like OX40 agonist) seems to be immediately following radiation therapy [ 52 , 74 ].…”

Section: Increasing the Rt And Ici Synergism: Schedule Ici Partnementioning

confidence: 99%

Enhance the Immune Checkpoint Inhibitors Efficacy with Radiotherapy Induced Immunogenic Cell Death: A Comprehensive Review and Latest Developments

Procureur

Simonaggio

Bibault

et al. 2021

Cancers

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The immunogenic cell death (ICD) is defined as a regulated cell death able to induce an adaptive immunity. It depends on different parameters including sufficient antigenicity, adjuvanticity and favorable microenvironment conditions. Radiation therapy (RT), a pillar of modern cancer treatment, is being used in many tumor types in curative, (neo) adjuvant, as well as metastatic settings. The anti-tumor effects of RT have been traditionally attributed to the mitotic cell death resulting from the DNA damages triggered by the release of reactive oxygen species. Recent evidence suggests that RT may also exert its anti-tumor effect by recruiting tumor-specific immunity. RT is able to induce the release of tumor antigens, to act as an immune adjuvant and thus to synergize with the anti-tumor immunity. The advent of new efficient immunotherapeutic agents, such as immune checkpoint inhibitors (ICI), in multiple tumor types sheds new light on the opportunity of combining RT and ICI. Here, we will describe the biological and radiobiological rationale of the RT-induced ICD. We will then focus on the interest to combine RT and ICI, from bench to bedside, and summarize the clinical data existing with this combination. Finally, RT technical adaptations to optimize the ICD induction will be discussed.

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“…However, limited to lower proportion of dMMR (about 15%), the effectiveness of PD-1/PD-L1 inhibitors treating CRC especially LARC is still uncertain. Interestingly, radiotherapy was found to enlarge the anti-PD1/PDL1 treatment effect by promoting different links in the immune response such as activation and recruitment of T cells, promotion of dendritic cells maturation, antigen exposure and upregulation of major histocompatibility complex molecules [ 25 , 26 ]. In addition, radiotherapy can also reduce tumor burden and reinvigorate exhausted T cells to strengthen the anti-PD1/PDL1 therapeutic efficacy [ 27 , 28 ].…”

Section: Introductionmentioning

confidence: 99%

Rationale and design of a prospective, multicenter, phase II clinical trial of safety and efficacy evaluation of long course neoadjuvant chemoradiotherapy plus tislelizumab followed by total mesorectal excision for locally advanced rectal cancer (NCRT-PD1-LARC trial)

Yang

Zhang

et al. 2022

BMC Cancer

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Background Long course radiotherapy plus neoadjuvant chemotherapy followed by resection (total mesorectal excision, TME) has accepted widespread recognized in the treatment of locally advanced rectal cancer (LARC). Tislelizumab, an anti-PD1 humanized IgG4 monoclonal antibody, has been demonstrated with clinical activity and is approved for treating recurrent/refractory classical Hodgkin lymphoma and locally advanced/metastatic urothelial carcinoma in China. However, the safety and efficacy of long course (neoadjuvant chemoradiotherapy, NCRT) plus tislelizumab followed by TME for LARC is still uncertain. Methods This NCRT-PD1-LARC trial will be a prospective, multicenter and phase II clinical trial designed to evaluate the safety and efficacy of LARC patients treated with long course NCRT plus tislelizumab followed by TME. This trial will consecutively enroll 50 stage II/III LARC patients (cT3N0M0 and cT1-3N1-2M0) with the tumor distal location ≤ 7 cm from anal verge at 7 centers in China. The enrolled patients will receive long course radiotherapy (50 Gy/25 f, 2 Gy/f, 5 days/week) and three 21-day cycles capecitabine (1000 mg/m2, bid, po, day1-14) plus three 21-day cycles tislelizumab (200 mg, iv.gtt, day8), followed by TME 6–8 weeks after the end of radiotherapy. The primary efficacy endpoint will be the pathological complete response (pCR) rate, which is defined as absence of viable tumor cells in the primary tumor and lymph nodes. Discussion To our knowledge, this trial is the first multicenter clinical trial in China to assess the safety and efficacy of NCRT plus anti-PD1 therapy followed by TME to treat patients with LARC. NCRT followed by TME was recognized as the most recommended treatment against LARC while could not be completely satisfied in clinic. This study expects to provide a solid basis and encouraging outcomes for this promising combination of radiotherapy, chemotherapy and immunotherapy in LARC. Trial registration Name of the registry: ClinicalTrials.gov. Trial registration number: NCT04911517. Date of registration: 23 May 2021. URL of trial registry record: https://www.clinicaltrials.gov/ct2/show/NCT04911517?id=BFH-NCRTPD&draw=2&rank=1.

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Potential and unsolved problems of anti-PD-1/PD-L1 therapy combined with radiotherapy

Cited by 9 publications

References 90 publications

Improving the synergistic combination of programmed death‐1/programmed death ligand‐1 blockade and radiotherapy by targeting the hypoxic tumour microenvironment

Improving the synergistic combination of programmed death‐1/programmed death ligand‐1 blockade and radiotherapy by targeting the hypoxic tumour microenvironment

Enhance the Immune Checkpoint Inhibitors Efficacy with Radiotherapy Induced Immunogenic Cell Death: A Comprehensive Review and Latest Developments

Rationale and design of a prospective, multicenter, phase II clinical trial of safety and efficacy evaluation of long course neoadjuvant chemoradiotherapy plus tislelizumab followed by total mesorectal excision for locally advanced rectal cancer (NCRT-PD1-LARC trial)

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