Impact of lymphopenia on efficacy of nivolumab in head and neck cancer patients.

INTRODUCTION: Lymphopenia has been correlated with poorer survival in patients with metastatic cancers treated with anti-PD-1 immunotherapy. Treatments such as chemotherapy, surgery or radiotherapy can induce lymphopenia. Radiation-induced lymphopenia is common and prolonged in head and neck cancer (HNSCC) patients. We evaluated the impact of lymphopenia, on efficacy of anti PD-1 nivolumab immunotherapy in HNSCC patients. METHODS: a multicenter retrospective study included consecutive patients treated with nivolumab for recurrent/metastatic (R/M) HNSCC between January 2017 and June 2019. Lymphopenia was defined as lymphocyte counts below 1000 cells/mm3 upon initiation of nivolumab. Logistical regression was performed on factors associated with lymphopenia and ROC analyses assessed association between lymphopenia and survival. RESULTS: median age was 65. Of the 100 included patients, 60% had been treated by surgery, 67% had had first-line chemotherapy, and 89% loco-regional radiotherapy, 65% had concurrent chemotherapy with radiotherapy. Lymphopenia occurred in 56 (56%) patients upon initiation of nivolumab, with 29 (29%) patients having radiation-related lymphopenia. Prior locoregional radiotherapy was the only factor associated with lymphopenia upon initiation of nivolumab by logistical regression (OR 0.144 [0.029-0.706], p - 0.017). Lymphopenia upon initiation of nivolumab did not affect progression-free survival (PFS) (p - 0.815), overall survival (OS) (p - 0.783) or disease control rate (DCR) (p - 0.125). Locoregional symptomatology (HR - 2.37 [1.24-4.54], p - 0.009), metastatic symptomatology (HR - 4.74 [2.21-10.15], and persistent lymphopenia under nivolumab (HR 3.96 [1.19-13.17] p - 0.034) were associated with poorer OS in multivariate analysis. CONCLUSIONS: Lymphopenia upon initiation of nivolumab was not associated with poorer survival in R/M HNSCC patients, but persistence of lymphopenia during immunotherapy might be a prognostic marker of patient survival.

Radioresistance of Non-Small Cell Lung Cancers and Therapeutic Perspectives.

Survival in unresectable locally advanced stage non-small cell lung cancer (NSCLC) patients remains poor despite chemoradiotherapy. Recently, adjuvant immunotherapy improved survival for these patients but we are still far from curing most of the patients with only a 57% survival remaining at 3 years. This poor survival is due to the resistance to chemoradiotherapy, local relapses, and distant relapses. Several biological mechanisms have been found to be involved in the chemoradioresistance such as cancer stem cells, cancer mutation status, or the immune system. New drugs to overcome this radioresistance in NSCLCs have been investigated such as radiosensitizer treatments or immunotherapies. Different modalities of radiotherapy have also been investigated to improve efficacity such as dose escalation or proton irradiations. In this review, we focused on biological mechanisms such as the cancer stem cells, the cancer mutations, the antitumor immune response in the first part, then we explored some strategies to overcome this radioresistance in stage III NSCLCs with new drugs or radiotherapy modalities.

[Mechanisms of radiation-induced lymphopenia and therapeutic impact]. / Mécanismes de la lymphopénie radio-induite et implications thérapeutiques.

Radiation induced lymphopenia is frequent and can be severe and durable. Although lymphocytes have long been known as highly radiosensitive cells, it is poorly characterized. Radiation-induced lymphopenia seems to affect lymphocyte subpopulations differently and seems to be influenced by radiation modalities. The depth and duration of lymphopenia depend on the location of the irradiation and the volumes of treatment. Importantly, radiation-induced lymphopenia has been associated with poorer prognosis in several tumor types. The knowledge about radiation-induced lymphopenia might lead to a rethinking of the modalities of radiotherapy and new approaches to restore lymphocytes counts.

Hadrontherapy Interactions in Molecular and Cellular Biology.

The resistance of cancer cells to radiotherapy is a major issue in the curative treatment of cancer patients. This resistance can be intrinsic or acquired after irradiation and has various definitions, depending on the endpoint that is chosen in assessing the response to radiation. This phenomenon might be strengthened by the radiosensitivity of surrounding healthy tissues. Sensitive organs near the tumor that is to be treated can be affected by direct irradiation or experience nontargeted reactions, leading to early or late effects that disrupt the quality of life of patients. For several decades, new modalities of irradiation that involve accelerated particles have been available, such as proton therapy and carbon therapy, raising the possibility of specifically targeting the tumor volume. The goal of this review is to examine the up-to-date radiobiological and clinical aspects of hadrontherapy, a discipline that is maturing, with promising applications. We first describe the physical and biological advantages of particles and their application in cancer treatment. The contribution of the microenvironment and surrounding healthy tissues to tumor radioresistance is then discussed, in relation to imaging and accurate visualization of potentially resistant hypoxic areas using dedicated markers, to identify patients and tumors that could benefit from hadrontherapy over conventional irradiation. Finally, we consider combined treatment strategies to improve the particle therapy of radioresistant cancers.

Sensitization of chondrosarcoma cells with PARP inhibitor and high-LET radiation.

Chondrosarcoma is a malignant tumor that arises from cartilaginous tissue and is radioresistant and chemoresistant to conventional treatments. The preferred treatment consists of surgical resection, which might cause severe disabilities for the patient; in addition, this procedure might be impossible for inoperable locations, such as the skull base. Carbon ion irradiation (hadron therapy) has been proposed as an alternative treatment, primarily due to its greater biological effectiveness and improved ballistic properties compared with conventional radiotherapy with X-rays. The goal of this study was to characterize the genetic mutations of a grade III chondrosarcoma cell line (CH2879) and examine the cellular responses to conventional radiotherapy (X-rays) and hadron therapy (proton and carbon ions) in the presence of the PARP inhibitor Olaparib. To better understand PARP inhibition, we first analyzed the formation of poly-ADP ribose chains by western blot; we observed an increase in its signal after irradiation, which disappeared on addition of the PARP inhibitor. PARPi enhanced ratio of approximately 1.3, 1.8, and 1.5 following irradiation of cells with X-rays, protons, and C-ions, respectively, as detected by clonogenic assay. The decrease in cell survival was confirmed by proliferation assay. The radiosensitivity of CH2879 cells was associated with mutations in homologous recombination repair genes, such as RAD50, SMARCA2 and NBN. This study demonstrates the capacity of the PARP inhibitor Olaparib to radiosensitize mutated chondrosarcoma cells to conventional photon irradiation, proton and carbon ion irradiation.

Combining PARP inhibition, radiation, and immunotherapy: A possible strategy to improve the treatment of cancer?

Immunotherapy has revolutionized the practice of oncology, improving survival in certain groups of patients with cancer. Immunotherapy can synergize with radiation therapy, increase locoregional control, and have abscopal effects. Combining it with other treatments, such as targeted therapies, is a promising means of improving the efficacy of immunotherapy. Because the value of immunotherapy is amplified with the expression of tumor antigens, coupling poly(ADP-ribose) polymerase (PARP) inhibitors and immunotherapy might be a promising treatment for cancer. Further, PARP inhibitors (PARPis) are being combined with radiation therapy to inhibit DNA repair functions, thus enhancing the effects of radiation; this association might interact with the antitumor immune response. Cytotoxic T lymphocytes are central to the antitumor immune response. PARP inhibitors and ionizing radiation can enhance the infiltration of cytotoxic T lymphocytes into the tumor bed, but they can also enhance PD-1/PDL-1 expression. Thus, the addition of immune checkpoint inhibitors with PARP inhibitors and/or ionizing radiation could counterbalance such immunosuppressive effects. With the present review article, we proposed to evaluate some of these associated therapies, and we explored the biological mechanisms and medical benefits of the potential combination of radiation therapy, immunotherapy, and PARP inhibitors.