- Email: [email protected]
129 speaker ABSCOPAL IMMUNE RESPONSE LINKED TO RADIOTHERAPY
S 48
S YMPOSIUM
ALK translocations: 57% objective response in 82 patients with a median duration of treatment of 5,7 months and a predicted 67% PFS rate at 6 months. Many other abnormalities linked to tyrosine kinase receptors could be used for selection of specific therapy such as amplification or activation mutation of HER2, HER3, HER4, FGFR 1, FGFR2, KDR& 128 speaker IMPROVING THE OUTCOME WITH CURATIVE HIGH PRECISION RADIOTHERAPY FOR METASTATIC PATIENTS? E. Lartigau Abstract not received.
M ONDAY, M AY 9, 2011
response to radiation and CTLA-4 blockade. Clin Cancer Res. 2009 Jan 15;15(2):597-606. 6. Matsumura S, et al. Radiation-induced CXCL16 release by breast cancer cells attracts effector T cells. J Immunol. 2008 Sep 1;181(5):3099-107. 7. Dewan MZ, et al. Fractionated but not single-dose radiotherapy induces an immune-mediated abscopal effect when combined with anti-CTLA-4 antibody. Clin Cancer Res. 2009 Sep 1;15(17):5379-88. 130 speaker CAN SMALL DOSES OF RADIATION ENHANCE CHEMOTHERAPY IN ADVANCED PATIENTS? V. Valentini1 1 P OLICLINICO U NIVERSITARIO "AGOSTINO G EMELLI ", C ATHOLIC U NIVER SITY, Radiation Oncology, Roma, Italy
129 speaker ABSCOPAL IMMUNE RESPONSE LINKED TO RADIOTHERAPY S. Formenti1 1 N EW YORK U NIVERSITY S CHOOL OF M EDICINE, New York, NY, USA
Over the past ten years we have developed a clinical translational program based on the rationale of immunizing patients against their own tumor by concomitantly: 1) removing existing "breaks" in their immune system and, 2) harnessing local RT-induced physical and biological perturbations at the irradiated tumor site, to achieve the successful conversion of the original tumor into an immunogenic hub (1, 2). To mimic the common clinical setting of established, metastatic cancer, we have employed as a model the poorly immunogenic 4T1 mouse mammary carcinoma. After s.c. inoculation 4T1 cells grow to form a highly invasive primary tumor that early on sheds spontaneous metastases to the lungs, and other organs (3). Mice usually die of metastatic disease to the lungs. 9H10 mAb against CTLA-4 releases a negative regulator of T cell activation. We demonstrated the effects of combining RT with CTLA-4 blockade given two weeks after implantation in mice, when primary tumors are palpable and metastatic cells have already spread systemically (4). Whereas single modality treatment was ineffective, RT and CTLA-4 blockade elicited CD8 T-cell-dependent antitumor immunity. The immune response effectively inhibited the growth of spontaneous lung metastases prolonging the survival time of animals. However, cure was rare, and most mice eventually succumbed to their disease (4). In the same models we found that RT enhanced the secretion by cancer cells of CXCL16, a chemokine that binds to CXCR6 on Th1 and activated CD8 effector T cells, and mediates their recruitment to sites of inflammation. CXCR6-deficient mice showed reduced infiltration of tumors by activated CD8 T cells and impaired tumor regression after RT and 9H10 (5). The contribution of invariant natural killer T (iNKT) cells, a subset with unique regulatory functions, in the response to RT and CTLA-4 blockade was then investigated. Growth of 4T1 primary tumors and lung metastases was compared in wild type (WT) and iNKT cells-deficient (iNKT/) mice, resulting in long-term survival, and resistance to a challenge with 4T1 cells (6). In preparation to a clinical translation of these findings we hypothesized that the type of dose fractionation regimen determines the ability of radiotherapy to synergize with antiCTLA-4 antibody. Using TSA mouse breast carcinoma and MCA38 mouse colon carcinoma models, cells were injected s.c. into syngeneic mice at two separate sites, defined as a "primary" site that was irradiated and a "secondary" site outside the radiotherapy field. Mice were randomly assigned to eight groups receiving no radiotherapy or three distinct regimens of radiotherapy (20 Gy in a single fraction, 8 Gy in 3 fractions, or 6 Gy in five 5 fractions, on consecutive days), +/- 9H10. In neither of the two models tested, treatment with 9H10 alone had detectable effect. Each of the radiotherapy regimens caused comparable growth delay of the primary tumors but had no effect on the secondary tumors, outside the radiation field. Conversely, 9H10 with either fractionated RT regimens (but not with single dose RT) achieved enhanced tumor response at the primary and secondary site (P < 0.0001). The frequency of CD8+ T cells showing tumor-specific IFNgamma production was proportional to the inhibition of the secondary tumor (7). The findings on dose and fractionation were translated to a preclinical experiment, that tests the combination of radiotherapy and fresolimumab, a monoclonal antibody against TGFβ . A clinical trial to test this combination in metastatic breast cancer is ongoing, aiming at detecting abscopal responses in metastases outside the radiation field. 1. Demaria S, Bhardwaj N, McBride WH, Formenti SC. Combining radiotherapy and immunotherapy: a revived partnership. Int J Radiat Oncol Biol Phys 2005;63:655666. 2. Formenti SC, Demaria S. Systemic effects of local radiotherapy. Lancet Oncol. 2009 Jul;10(7):718-26. 3. Aslakson CJ, Miller FR. Selective events in the metastatic process defined by analysis of the sequential dissemination of subpopulations of a mouse mammary tumor. Cancer Res 1992;52:13991405. 4. Demaria S et al. Immune-mediated inhibition of metastases following treatment with local radiation and CTLA-4 blockade in a mouse model of breast cancer. Clin Cancer Res 2005;11:728734. 5. Pilones KA, et al. Invariant natural killer T cells regulate breast cancer
Improvements in the methodology of clonogenic assays within the last decade have made it possible to observe that the efficacy in killing clonogenic cells of radiation doses below 0,5 Gy is larger than predicted by the linear quadratic model for a variety of tumour cell lines in vitro. In other words, radiation doses below 0,5 Gy seems to be more effective per unit dose than higher doses. This phenomenon is known as "Low Dose Hyper-Radio Sensitivity" (LD-HRS). Low-dose radiotherapy (LDR) (<50 cGy) induces enhanced cell killing in vitro via the hyper-radiation sensitivity phenomenon. The exact molecular mechanisms underling the HRS phenomenon is still unclear. LD-FRT has been demonstrated to enhance the effectiveness of multiple chemotherapeutic agents, including Carboplatin, Cisplatin, Docetaxel, Etoposide, Gemcitabine and Paclitaxel, across a variety of tumor cell lines. Even if the outcome of clinical results with only LD-FRT are controversial, preliminary results of clinical trials combining LD-FRT with chemotherapy suggest that this treatment could be both feasible and effective. Although far from being conclusive, these first evidence are promising and support the opportunity of further phase II studies exploring LD-FRT with concurrent chemotherapy as a new treatment modality.
S YMPOSIUM
ALK translocations: 57% objective response in 82 patients with a median duration of treatment of 5,7 months and a predicted 67% PFS rate at 6 months. Many other abnormalities linked to tyrosine kinase receptors could be used for selection of specific therapy such as amplification or activation mutation of HER2, HER3, HER4, FGFR 1, FGFR2, KDR& 128 speaker IMPROVING THE OUTCOME WITH CURATIVE HIGH PRECISION RADIOTHERAPY FOR METASTATIC PATIENTS? E. Lartigau Abstract not received.
M ONDAY, M AY 9, 2011
response to radiation and CTLA-4 blockade. Clin Cancer Res. 2009 Jan 15;15(2):597-606. 6. Matsumura S, et al. Radiation-induced CXCL16 release by breast cancer cells attracts effector T cells. J Immunol. 2008 Sep 1;181(5):3099-107. 7. Dewan MZ, et al. Fractionated but not single-dose radiotherapy induces an immune-mediated abscopal effect when combined with anti-CTLA-4 antibody. Clin Cancer Res. 2009 Sep 1;15(17):5379-88. 130 speaker CAN SMALL DOSES OF RADIATION ENHANCE CHEMOTHERAPY IN ADVANCED PATIENTS? V. Valentini1 1 P OLICLINICO U NIVERSITARIO "AGOSTINO G EMELLI ", C ATHOLIC U NIVER SITY, Radiation Oncology, Roma, Italy
129 speaker ABSCOPAL IMMUNE RESPONSE LINKED TO RADIOTHERAPY S. Formenti1 1 N EW YORK U NIVERSITY S CHOOL OF M EDICINE, New York, NY, USA
Over the past ten years we have developed a clinical translational program based on the rationale of immunizing patients against their own tumor by concomitantly: 1) removing existing "breaks" in their immune system and, 2) harnessing local RT-induced physical and biological perturbations at the irradiated tumor site, to achieve the successful conversion of the original tumor into an immunogenic hub (1, 2). To mimic the common clinical setting of established, metastatic cancer, we have employed as a model the poorly immunogenic 4T1 mouse mammary carcinoma. After s.c. inoculation 4T1 cells grow to form a highly invasive primary tumor that early on sheds spontaneous metastases to the lungs, and other organs (3). Mice usually die of metastatic disease to the lungs. 9H10 mAb against CTLA-4 releases a negative regulator of T cell activation. We demonstrated the effects of combining RT with CTLA-4 blockade given two weeks after implantation in mice, when primary tumors are palpable and metastatic cells have already spread systemically (4). Whereas single modality treatment was ineffective, RT and CTLA-4 blockade elicited CD8 T-cell-dependent antitumor immunity. The immune response effectively inhibited the growth of spontaneous lung metastases prolonging the survival time of animals. However, cure was rare, and most mice eventually succumbed to their disease (4). In the same models we found that RT enhanced the secretion by cancer cells of CXCL16, a chemokine that binds to CXCR6 on Th1 and activated CD8 effector T cells, and mediates their recruitment to sites of inflammation. CXCR6-deficient mice showed reduced infiltration of tumors by activated CD8 T cells and impaired tumor regression after RT and 9H10 (5). The contribution of invariant natural killer T (iNKT) cells, a subset with unique regulatory functions, in the response to RT and CTLA-4 blockade was then investigated. Growth of 4T1 primary tumors and lung metastases was compared in wild type (WT) and iNKT cells-deficient (iNKT/) mice, resulting in long-term survival, and resistance to a challenge with 4T1 cells (6). In preparation to a clinical translation of these findings we hypothesized that the type of dose fractionation regimen determines the ability of radiotherapy to synergize with antiCTLA-4 antibody. Using TSA mouse breast carcinoma and MCA38 mouse colon carcinoma models, cells were injected s.c. into syngeneic mice at two separate sites, defined as a "primary" site that was irradiated and a "secondary" site outside the radiotherapy field. Mice were randomly assigned to eight groups receiving no radiotherapy or three distinct regimens of radiotherapy (20 Gy in a single fraction, 8 Gy in 3 fractions, or 6 Gy in five 5 fractions, on consecutive days), +/- 9H10. In neither of the two models tested, treatment with 9H10 alone had detectable effect. Each of the radiotherapy regimens caused comparable growth delay of the primary tumors but had no effect on the secondary tumors, outside the radiation field. Conversely, 9H10 with either fractionated RT regimens (but not with single dose RT) achieved enhanced tumor response at the primary and secondary site (P < 0.0001). The frequency of CD8+ T cells showing tumor-specific IFNgamma production was proportional to the inhibition of the secondary tumor (7). The findings on dose and fractionation were translated to a preclinical experiment, that tests the combination of radiotherapy and fresolimumab, a monoclonal antibody against TGFβ . A clinical trial to test this combination in metastatic breast cancer is ongoing, aiming at detecting abscopal responses in metastases outside the radiation field. 1. Demaria S, Bhardwaj N, McBride WH, Formenti SC. Combining radiotherapy and immunotherapy: a revived partnership. Int J Radiat Oncol Biol Phys 2005;63:655666. 2. Formenti SC, Demaria S. Systemic effects of local radiotherapy. Lancet Oncol. 2009 Jul;10(7):718-26. 3. Aslakson CJ, Miller FR. Selective events in the metastatic process defined by analysis of the sequential dissemination of subpopulations of a mouse mammary tumor. Cancer Res 1992;52:13991405. 4. Demaria S et al. Immune-mediated inhibition of metastases following treatment with local radiation and CTLA-4 blockade in a mouse model of breast cancer. Clin Cancer Res 2005;11:728734. 5. Pilones KA, et al. Invariant natural killer T cells regulate breast cancer
Improvements in the methodology of clonogenic assays within the last decade have made it possible to observe that the efficacy in killing clonogenic cells of radiation doses below 0,5 Gy is larger than predicted by the linear quadratic model for a variety of tumour cell lines in vitro. In other words, radiation doses below 0,5 Gy seems to be more effective per unit dose than higher doses. This phenomenon is known as "Low Dose Hyper-Radio Sensitivity" (LD-HRS). Low-dose radiotherapy (LDR) (<50 cGy) induces enhanced cell killing in vitro via the hyper-radiation sensitivity phenomenon. The exact molecular mechanisms underling the HRS phenomenon is still unclear. LD-FRT has been demonstrated to enhance the effectiveness of multiple chemotherapeutic agents, including Carboplatin, Cisplatin, Docetaxel, Etoposide, Gemcitabine and Paclitaxel, across a variety of tumor cell lines. Even if the outcome of clinical results with only LD-FRT are controversial, preliminary results of clinical trials combining LD-FRT with chemotherapy suggest that this treatment could be both feasible and effective. Although far from being conclusive, these first evidence are promising and support the opportunity of further phase II studies exploring LD-FRT with concurrent chemotherapy as a new treatment modality.