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Mohammad K. Khan - One of the best experts on this subject based on the ideXlab platform.
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Abstract 526: Tumor-draining Lymph Node Irradiation reduces tumor-infiltrating stem-like CD8+T-cells and abrogates the abscopal effect
Clinical Research (Excluding Clinical Trials), 2019Co-Authors: Zachary S. Buchwald, Tahseen H. Nasti, Christiane Sigrid Eberhardt, David H. Lawson, Walter J. Curran, Rafi Ahmed, Andreas Wieland, Mohammad K. KhanAbstract:Purpose: PD-1 and PD-L1 antagonists are efficacious because cancer induces T-cell exhaustion via upregulation of PD-L1 and persistent antigen exposure. Our lab, has shown that the proliferative burst following αPD-L1 therapy of exhausted CD8+PD-1+T-cells is restricted to a “stem-like” CD8+T-cell subset in a murine chronic viral infection model. The role of these stem-like CD8+T-cells in malignancies and whether these cells respond to other immuno-stimulation including radiotherapy (RT) is unknown. RT’s immuno-stimulation includes acting as an in-situ vaccine by liberating cryptic tumor neo-antigens, generating a potent anti-tumor CD8+T-cell response, synergizing with αPD-1/L1 and leading to control at distant sites of disease outside the radiation field (abscopal effect). In initial studies, we found these stem-like CD8+T-cells in B16F10 tumors and at high frequencies in the tumor-draining Lymph Nodes (TDLN) of immunocompetent mice. Here, we investigated: (1) the impact of tumor-directed RT on this stem-like CD8+T-cell population in the tumor and TDLN in the context of an abscopal response, and (2) due to the high frequency of stem-like CD8+T-cells in the TDLN, whether depletion of Lymphocytes from the TDLN via RT influenced the abscopal effect. Experimental Design: We developed a preclinical model of oligo-metastatic melanoma to evaluate the role of stem-like CD8+ T-cells and the TDLN in the abscopal effect. This was done with unilateral tumor-directed RT with or without TDLN-directed RT. This was also done in the presence and absence of αPD-L1. Results: Tumor-directed RT improved local tumor control and induced an abscopal response with a concomitant increase in tumor infiltrating tumor-specific stem-like CD8+T-cells. Tumor-specific stem-like CD8+T-cells were also observed in the TDLN of tumors on both sides. Importantly, the tumor-directed RT increased tumor-specific T-cell proliferation in the TDLNs bilaterally despite only being targeted at one tumor. Given this robust proliferative response and the high frequency of stem-like CD8+T-cells in the TDLN, we next evaluated the role of the TDLN in mediating the abscopal effect. We found that the abscopal effect is impaired if the TDLN is Lymphocyte depleted with TDLN-directed RT in the presence or absence of αPD-L1. Additionally, the tumor-directed RT mediated increase in stem-like T-cells in the irradiated and unirradiated tumor was abrogated with TDLN-directed RT. Conclusion: Our results demonstrate slowed distant tumor growth following Irradiation of a local site and that this correlates with an increase in tumor-infiltrating stem-like CD8+T-cells which is reduced with TDLN-directed RT. These data suggest a critical role for both the stem-like CD8+T-cells and the TDLN in mediating the abscopal effect. Citation Format: Zachary S. Buchwald, Tahseen H. Nasti, Christiane S. Eberhardt, Andreas Wieland, David Lawson, Walter Curran, Rafi Ahmed, Mohammad K. Khan. Tumor-draining Lymph Node Irradiation reduces tumor-infiltrating stem-like CD8+T-cells and abrogates the abscopal effect [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 526.
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abstract 526 tumor draining Lymph Node Irradiation reduces tumor infiltrating stem like cd8 t cells and abrogates the abscopal effect
Cancer Research, 2019Co-Authors: Zachary S. Buchwald, Tahseen H. Nasti, Christiane Sigrid Eberhardt, David H. Lawson, Walter J. Curran, Rafi Ahmed, Andreas Wieland, Mohammad K. KhanAbstract:Purpose: PD-1 and PD-L1 antagonists are efficacious because cancer induces T-cell exhaustion via upregulation of PD-L1 and persistent antigen exposure. Our lab, has shown that the proliferative burst following αPD-L1 therapy of exhausted CD8+PD-1+T-cells is restricted to a “stem-like” CD8+T-cell subset in a murine chronic viral infection model. The role of these stem-like CD8+T-cells in malignancies and whether these cells respond to other immuno-stimulation including radiotherapy (RT) is unknown. RT’s immuno-stimulation includes acting as an in-situ vaccine by liberating cryptic tumor neo-antigens, generating a potent anti-tumor CD8+T-cell response, synergizing with αPD-1/L1 and leading to control at distant sites of disease outside the radiation field (abscopal effect). In initial studies, we found these stem-like CD8+T-cells in B16F10 tumors and at high frequencies in the tumor-draining Lymph Nodes (TDLN) of immunocompetent mice. Here, we investigated: (1) the impact of tumor-directed RT on this stem-like CD8+T-cell population in the tumor and TDLN in the context of an abscopal response, and (2) due to the high frequency of stem-like CD8+T-cells in the TDLN, whether depletion of Lymphocytes from the TDLN via RT influenced the abscopal effect. Experimental Design: We developed a preclinical model of oligo-metastatic melanoma to evaluate the role of stem-like CD8+ T-cells and the TDLN in the abscopal effect. This was done with unilateral tumor-directed RT with or without TDLN-directed RT. This was also done in the presence and absence of αPD-L1. Results: Tumor-directed RT improved local tumor control and induced an abscopal response with a concomitant increase in tumor infiltrating tumor-specific stem-like CD8+T-cells. Tumor-specific stem-like CD8+T-cells were also observed in the TDLN of tumors on both sides. Importantly, the tumor-directed RT increased tumor-specific T-cell proliferation in the TDLNs bilaterally despite only being targeted at one tumor. Given this robust proliferative response and the high frequency of stem-like CD8+T-cells in the TDLN, we next evaluated the role of the TDLN in mediating the abscopal effect. We found that the abscopal effect is impaired if the TDLN is Lymphocyte depleted with TDLN-directed RT in the presence or absence of αPD-L1. Additionally, the tumor-directed RT mediated increase in stem-like T-cells in the irradiated and unirradiated tumor was abrogated with TDLN-directed RT. Conclusion: Our results demonstrate slowed distant tumor growth following Irradiation of a local site and that this correlates with an increase in tumor-infiltrating stem-like CD8+T-cells which is reduced with TDLN-directed RT. These data suggest a critical role for both the stem-like CD8+T-cells and the TDLN in mediating the abscopal effect. Citation Format: Zachary S. Buchwald, Tahseen H. Nasti, Christiane S. Eberhardt, Andreas Wieland, David Lawson, Walter Curran, Rafi Ahmed, Mohammad K. Khan. Tumor-draining Lymph Node Irradiation reduces tumor-infiltrating stem-like CD8+T-cells and abrogates the abscopal effect [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 526.
Hercilio Martelli - One of the best experts on this subject based on the ideXlab platform.
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paediatric dysgerminoma results of three consecutive french germ cell tumours clinical studies tgm 85 90 95 with late effects study
European Journal of Cancer, 2018Co-Authors: Gwenaelle Duhil De Benaze, Helene Pacquement, Claire Berger, Helene Sudourbonnange, Cecile Verite, Cecile Faureconter, Daniel Orbach, Nadege Corradini, Catharine Patte, Hercilio MartelliAbstract:Abstract Methods French patients (≤18years) treated for dysgerminoma between 1985 and 2005 in TGM-85, 90, 95 protocols were included. Treatment was based on primary unilateral oophorectomy followed by prophylactic Lymph Node Irradiation (1985–1998) or a wait-and-see strategy (1998–2005) for localised completely resected tumours (pS1) or by platinum-based chemotherapy for advanced diseases. Results Forty-eight patients (median age 12.8 years) were included. Six patients had gonadal dysgenesis. Two had bilateral dysgerminoma. Twenty-eight patients had loco-regional dissemination, seven with para-aortic Lymph Nodes. None had distant metastases. Primary surgery was performed in 47/48 patients. Among the 15 patients with pS1 tumour: seven did not receive adjuvant treatment, six had Lymph Node Irradiation and two received chemotherapy. Among the 32 patients with advanced tumour, 31 received cisplatinum-based (n = 25) or carboplatin-based (n = 8) regimen with Lymph Node Irradiation for one of them and one did not receive adjuvant treatment. With a median follow-up of 14 years, all patients are alive in complete remission. Five events occurred: 2 contralateral dysgerminomas, 1 peritoneal relapse and 2 second neoplasms (teratoma and melanoma). Bilateral oophorectomy was necessary for 12 patients. Desire of pregnancy was expressed for 17/36 patients with unilateral oophorectomy, which succeeded in 13 cases (5 medically assisted). 2/17 had ovarian failure. The renal function was normal in 24/25 evaluated patients treated with platinum, ifosfamide or Irradiation. The hearing function was evaluated on 17/36 patients treated with platinum: 12 Brock grade-0, 3 brock grade-1 and 2 grade-4. Conclusion Dysgerminoma has an excellent prognosis even in advanced cases with conservative surgery and platinum-based chemotherapy. However the disease and/or treatment resulted in a high rate of bilateral oophorectomies and a significant impact on future fertility.
Gwenaelle Duhil De Benaze - One of the best experts on this subject based on the ideXlab platform.
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paediatric dysgerminoma results of three consecutive french germ cell tumours clinical studies tgm 85 90 95 with late effects study
European Journal of Cancer, 2018Co-Authors: Gwenaelle Duhil De Benaze, Helene Pacquement, Claire Berger, Helene Sudourbonnange, Cecile Verite, Cecile Faureconter, Daniel Orbach, Nadege Corradini, Catharine Patte, Hercilio MartelliAbstract:Abstract Methods French patients (≤18years) treated for dysgerminoma between 1985 and 2005 in TGM-85, 90, 95 protocols were included. Treatment was based on primary unilateral oophorectomy followed by prophylactic Lymph Node Irradiation (1985–1998) or a wait-and-see strategy (1998–2005) for localised completely resected tumours (pS1) or by platinum-based chemotherapy for advanced diseases. Results Forty-eight patients (median age 12.8 years) were included. Six patients had gonadal dysgenesis. Two had bilateral dysgerminoma. Twenty-eight patients had loco-regional dissemination, seven with para-aortic Lymph Nodes. None had distant metastases. Primary surgery was performed in 47/48 patients. Among the 15 patients with pS1 tumour: seven did not receive adjuvant treatment, six had Lymph Node Irradiation and two received chemotherapy. Among the 32 patients with advanced tumour, 31 received cisplatinum-based (n = 25) or carboplatin-based (n = 8) regimen with Lymph Node Irradiation for one of them and one did not receive adjuvant treatment. With a median follow-up of 14 years, all patients are alive in complete remission. Five events occurred: 2 contralateral dysgerminomas, 1 peritoneal relapse and 2 second neoplasms (teratoma and melanoma). Bilateral oophorectomy was necessary for 12 patients. Desire of pregnancy was expressed for 17/36 patients with unilateral oophorectomy, which succeeded in 13 cases (5 medically assisted). 2/17 had ovarian failure. The renal function was normal in 24/25 evaluated patients treated with platinum, ifosfamide or Irradiation. The hearing function was evaluated on 17/36 patients treated with platinum: 12 Brock grade-0, 3 brock grade-1 and 2 grade-4. Conclusion Dysgerminoma has an excellent prognosis even in advanced cases with conservative surgery and platinum-based chemotherapy. However the disease and/or treatment resulted in a high rate of bilateral oophorectomies and a significant impact on future fertility.
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Paediatric dysgerminoma: Results of three consecutive French germ cell tumours clinical studies (TGM-85/90/95) with late effects study.
European journal of cancer (Oxford England : 1990), 2018Co-Authors: Gwenaelle Duhil De Benaze, Helene Pacquement, Claire Berger, Cecile Verite, Daniel Orbach, Nadege Corradini, Catharine Patte, Cécile Faure-conter, Hélène Sudour-bonnange, Hélène MartelliAbstract:Abstract Methods French patients (≤18years) treated for dysgerminoma between 1985 and 2005 in TGM-85, 90, 95 protocols were included. Treatment was based on primary unilateral oophorectomy followed by prophylactic Lymph Node Irradiation (1985–1998) or a wait-and-see strategy (1998–2005) for localised completely resected tumours (pS1) or by platinum-based chemotherapy for advanced diseases. Results Forty-eight patients (median age 12.8 years) were included. Six patients had gonadal dysgenesis. Two had bilateral dysgerminoma. Twenty-eight patients had loco-regional dissemination, seven with para-aortic Lymph Nodes. None had distant metastases. Primary surgery was performed in 47/48 patients. Among the 15 patients with pS1 tumour: seven did not receive adjuvant treatment, six had Lymph Node Irradiation and two received chemotherapy. Among the 32 patients with advanced tumour, 31 received cisplatinum-based (n = 25) or carboplatin-based (n = 8) regimen with Lymph Node Irradiation for one of them and one did not receive adjuvant treatment. With a median follow-up of 14 years, all patients are alive in complete remission. Five events occurred: 2 contralateral dysgerminomas, 1 peritoneal relapse and 2 second neoplasms (teratoma and melanoma). Bilateral oophorectomy was necessary for 12 patients. Desire of pregnancy was expressed for 17/36 patients with unilateral oophorectomy, which succeeded in 13 cases (5 medically assisted). 2/17 had ovarian failure. The renal function was normal in 24/25 evaluated patients treated with platinum, ifosfamide or Irradiation. The hearing function was evaluated on 17/36 patients treated with platinum: 12 Brock grade-0, 3 brock grade-1 and 2 grade-4. Conclusion Dysgerminoma has an excellent prognosis even in advanced cases with conservative surgery and platinum-based chemotherapy. However the disease and/or treatment resulted in a high rate of bilateral oophorectomies and a significant impact on future fertility.
Feng-yi Feng - One of the best experts on this subject based on the ideXlab platform.
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Autologous peripheral blood stem cell transplantation in the treatment of patients with primary large mediastinal B-cell Lymphoma
Zhonghua zhong liu za zhi [Chinese journal of oncology], 2003Co-Authors: Yuankai Shi, Xiao-hong Han, Ai-ping Zhou, Shengyu Zhou, Peng Liu, Jianliang Yang, Feng-yi FengAbstract:Objective To evaluate the therapeutic effectiveness and safety of high dose chemoradiotherapy (HDC) combined with autologous peripheral blood stem cell transplantation (APBSCT) in the treatment of patients with primary large m ediastinal B-cell Lymphoma (PMLBL). Methods Among nine patients with PMLBL treated with APBSCT, high dose chemotherapy combined with total body Irradiation (TBI) o r total Lymph Node Irradiation (TLI)/subtotal Lymph Node Irradiation (STLI) were given to 7 patients and high dose chemotherapy only as pre-transplantation reg i men in 2 patients. All patients received supplementary Irradiation at the primar y mediastinum after transplantation. Results After a median follow-up of 24 (10-8 4) months, 5 patients achieved complete remission (CR) and 3 patients partial re mission (PR) after induction chemotherapy. One patient developed progressive dis ease before transplantation. All 5 patients who achieved CR after induction chem otherapy became disease-free survivors (DFS). One of 3 patients who achieved P R af ter induction chemotherapy was DFS, the other two died in the third and fifth mo nth, respectively. The patient who relapsed before transplantation died in the s ixth month carrying the disease all along. According to the life table method, t he cumulative probability of 7-year DFS and overall survival (OS) were both 66. 7%. No transplant-related mortality was found. Conclusion High dose chemoradiothe rapy combined with autologous peripheral blood stem cell transplantation is a hi ghly potential therapeutic treatment for poor prognostic primary mediastinal lar ge B-cell Lymphoma.
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High dose chemoradiotherapy with autologous hematopoietic stem cell transplantation in the treatment of advanced Hodgkin’s Lymphoma: A report of 11 cases
Chinese Journal of Cancer Research, 2002Co-Authors: Shengyu Zhou, Yuankai Shi, Xiao-hong Han, Ai-ping Zhou, Peng Liu, Jianliang Yang, Feng-yi FengAbstract:Objective: High dose therapy (HDT) with autologous hematopoietic stem cell transplantation (ASCT) has become one of the important salvage treatments for the Hodgkin’s Lymphoma patients with relapsed or resistant disease, but its role as the primary treatment remains indefinite. This study was designed to further evaluate its status in the combined modality treatment, especially, to discuss its value in the primary treatment of the patients who had advanced disease with poor prognostic factors. Methods: Eleven patients who had advanced or relapsed disease with poor prognostic factors were enrolled in this study. Among them, 9 cases had primary treatment, and 2 cases had secondary treatment; one patient received autologous bone marrow transplantation (ABMT), and 10 patients received autologous peripheral blood stem cell transplantation (APBSCT). After induction treatment 4 cases achieved complete response (CR) and 7 cases achieved partial response (PR). High dose chemotherapy combined with total body Irradiation (TBI) or total Lymph Node Irradiation (TLI)/subtotal Lymph Node Irradiation (STLI) were adopted in 7 cases and only high dose chemotherapy were adopted in 4 cases as the transplant preparative regimens. 5 cases received complementary Irradiation in the primary sites after transplant. Results: The patients who had CR before transplantation were given consolidative therapy. Among the rest with PR, 2 cases achieved CR, 1 case PR, and 4 cases SD. Furthermore all these patients who maintained SD had bone involvement. With a median follow-up for all patients of 13(1–80) months, all of them are alive currently. Four cases are event-free survival (EFS); 4 cases with bone involvement are progression-free survival (PFS); 3 cases experienced relapse after transplant, one of them is EFS for 42 months again after a local relapsed site Irradiation; the other two cases are being given further salvaged treatment now. According to the Life Tables method, the cumulative probability of 6-year PFS and OS is 55.68% and 100% respectively. The dominating transplant-related toxicity was bone marrow suppression in grades IV. No obvious cardiac, hepatic, and nephritic toxicity was found. No transplant related mortality. Conclusion: HDT combined with ASCT is a method worthwhile to further study for the treatment of the patients with advanced or relapsed Hodgkin’s Lymphoma with poor prognostic factors.
Ik Jae Lee - One of the best experts on this subject based on the ideXlab platform.
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Comparison of Dose Distribution in Regional Lymph Nodes in Whole-Breast Radiotherapy vs. Whole-Breast Plus Regional Lymph Node Irradiation: An In Silico Planning Study in Participating Institutions of the Phase III Randomized Trial (KROG 1701).
Cancers, 2020Co-Authors: Haeyoung Kim, Heejung Kim, Won Soon Park, Jong Yun Baek, Sung Ja Ahn, Mi Young Kim, Shin-hyung Park, Ik Jae Lee, Jin Hee KimAbstract:The purpose of the current in silico planning study is to compare radiation doses of whole-breast Irradiation (WBI) and whole-breast plus regional Lymph Node Irradiation (WBI+RNI) administered to the regional Lymph Nodes (RLN) in pN1 breast cancer. Twenty-four participating institutions were asked to create plans of WBI and WBI+RNI for two dummy cases. To compare target coverage between the participants, an isodose line equal to 90% of the prescribed dose was converted to an isodose contour (contour90% iso). The relative nodal dose (RND) was obtained using the ratio of RLN dose to the target dose. The Fleiss’s kappa values which represent inter-observer agreement of contour90% iso were over 0.68. For RNI, 6 institutions included axillary Lymph Node (ALN), supraclavicular Lymph Node (SCN), and internal mammary Lymph Node (IMN), while 18 hospitals included only ALN and SCN. The median RND between the WBI and WBI+RNI were as follows: 0.64 vs. 1.05 (ALN level I), 0.27 vs. 1.08 (ALN level II), 0.02 vs. 1.12 (ALN level III), 0.01 vs. 1.12 (SCN), and 0.54 vs. 0.82 (IMN). In all nodal regions, the RND was significantly lower in WBI than in WBI+RNI (p < 0.01). In this study, we could identify the nodal dose difference between WBI and WBI+RNI.
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Evaluation of optimal treatment planning for radiotherapy of synchronous bilateral breast cancer including regional Lymph Node Irradiation.
Radiation oncology (London England), 2019Co-Authors: Yeona Cho, Yoon Jin Cho, Won Suk Chang, Jun Won Kim, Won Hoon Choi, Ik Jae LeeAbstract:We evaluated the optimal radiotherapy (RT) plan for synchronous bilateral breast cancer (SBBC), especially treatment plans including the regional Lymph Node (LN) area. This study was conducted using 15 patients with SBBC (5 with small breasts, 5 with large breasts, and 5 who underwent a left total mastectomy). The clinical target volume (CTV) was defined as the volume enveloping the bilateral whole breasts/chest wall and left regional LN area. We established the following plans: 1) volumetric-modulated arc therapy (VMAT)-the only plan using two pairs of partial arcs for the whole target volume, 2) VMAT using one partial arc for the left CTV followed by a 3D tangential technique for the right breast (primary hybrid plan), and 3) VMAT for the left CTV followed by a tangential technique using an automatically calculated prescription dose for the right breast, considering the background dose from the left breast VMAT plan (modified hybrid plan). The Tukey test and one-way analysis of variance were used to compare the target coverage and doses to organs at risk (OARs) of the three techniques. For target coverage, the VMAT-only and modified hybrid plans showed comparable target coverage in terms of Dmean (50.33 Gy vs. 50.53 Gy, p = 0.106). The primary hybrid plan showed the largest distribution of the high-dose volume, with V105% of 25.69% and V110% of 6.37% for the planning target volume (PTV) (p
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evaluation of optimal treatment planning for radiotherapy of synchronous bilateral breast cancer including regional Lymph Node Irradiation
Radiation Oncology, 2019Co-Authors: Yeona Cho, Yoon Jin Cho, Won Suk Chang, Jun Won Kim, Won Hoon Choi, Ik Jae LeeAbstract:We evaluated the optimal radiotherapy (RT) plan for synchronous bilateral breast cancer (SBBC), especially treatment plans including the regional Lymph Node (LN) area. This study was conducted using 15 patients with SBBC (5 with small breasts, 5 with large breasts, and 5 who underwent a left total mastectomy). The clinical target volume (CTV) was defined as the volume enveloping the bilateral whole breasts/chest wall and left regional LN area. We established the following plans: 1) volumetric-modulated arc therapy (VMAT)-the only plan using two pairs of partial arcs for the whole target volume, 2) VMAT using one partial arc for the left CTV followed by a 3D tangential technique for the right breast (primary hybrid plan), and 3) VMAT for the left CTV followed by a tangential technique using an automatically calculated prescription dose for the right breast, considering the background dose from the left breast VMAT plan (modified hybrid plan). The Tukey test and one-way analysis of variance were used to compare the target coverage and doses to organs at risk (OARs) of the three techniques. For target coverage, the VMAT-only and modified hybrid plans showed comparable target coverage in terms of Dmean (50.33 Gy vs. 50.53 Gy, p = 0.106). The primary hybrid plan showed the largest distribution of the high-dose volume, with V105% of 25.69% and V110% of 6.37% for the planning target volume (PTV) (p < 0.001). For OARs including the lungs, heart, and left anterior descending artery, the percentages of volume at various doses (V5Gy, V10Gy, V20Gy, V30Gy) and Dmean were significantly lower in both the primary and modified hybrid plans compared to those of the VMAT-only plan. These results were consistent in subgroup analyses of breast size and morphological variation. The modified hybrid plan, using an automatically calculated prescription dose for the right breast and taking into consideration the background dose from the left breast VMAT plan, showed comparable target coverage to that of the VMAT-only plan, and was superior for saving OARs. However, considering that VMAT can be adjusted according to the physician’s intention, further evaluation is needed for developing a better plan.
