Clinical Development of Novel Drug-Radiotherapy Combinations.

Radiotherapy is a fundamental component of treatment for the majority of patients with cancer. In recent decades, technological advances have enabled patients to receive more targeted doses of radiation to the tumor, with sparing of adjacent normal tissues. There had been hope that the era of precision medicine would enhance the combination of radiotherapy with targeted anticancer drugs; however, this ambition remains to be realized. In view of this lack of progress, the FDA-AACR-ASTRO Clinical Development of Drug-Radiotherapy Combinations Workshop was held in February 2018 to bring together stakeholders and opinion leaders from academia, clinical radiation oncology, industry, patient advocacy groups, and the FDA to discuss challenges to introducing new drug-radiotherapy combinations to the clinic. This Perspectives in Regulatory Science and Policy article summarizes the themes and action points that were discussed. Intelligent trial design is required to increase the number of studies that efficiently meet their primary outcomes; endpoints to be considered include local control, organ preservation, and patient-reported outcomes. Novel approaches including immune-oncology or DNA-repair inhibitor agents combined with radiotherapy should be prioritized. In this article, we focus on how the regulatory challenges associated with defining a new drug-radiotherapy combination can be overcome to improve clinical outcomes for patients with cancer

Clinical development of new drug-radiotherapy combinations.

In countries with the best cancer outcomes, approximately 60% of patients receive radiotherapy as part of their treatment, which is one of the most cost-effective cancer treatments. Notably, around 40% of cancer cures include the use of radiotherapy, either as a single modality or combined with other treatments. Radiotherapy can provide enormous benefit to patients with cancer. In the past decade, significant technical advances, such as image-guided radiotherapy, intensity-modulated radiotherapy, stereotactic radiotherapy, and proton therapy enable higher doses of radiotherapy to be delivered to the tumour with significantly lower doses to normal surrounding tissues. However, apart from the combination of traditional cytotoxic chemotherapy with radiotherapy, little progress has been made in identifying and defining optimal targeted therapy and radiotherapy combinations to improve the efficacy of cancer treatment. The National Cancer Research Institute Clinical and Translational Radiotherapy Research Working Group (CTRad) formed a Joint Working Group with representatives from academia, industry, patient groups and regulatory bodies to address this lack of progress and to publish recommendations for future clinical research. Herein, we highlight the Working Group's consensus recommendations to increase the number of novel drugs being successfully registered in combination with radiotherapy to improve clinical outcomes for patients with cancer.National Institute for Health ResearchThis is the final version of the article. It first appeared from Nature Publishing Group via http://dx.doi.org/10.1038/nrclinonc.2016.7

Consensus guidelines for the detection of immunogenic cell death

none82siApoptotic cells have long been considered as intrinsically tolerogenic or unable to elicit immune responses specific for dead cell-associated antigens. However, multiple stimuli can trigger a functionally peculiar type of apoptotic demise that does not go unnoticed by the adaptive arm of the immune system, which we named "immunogenic cell death" (ICD). ICD is preceded or accompanied by the emission of a series of immunostimulatory damage-associated molecular patterns (DAMPs) in a precise spatiotemporal configuration. Several anticancer agents that have been successfully employed in the clinic for decades, including various chemotherapeutics and radiotherapy, can elicit ICD. Moreover, defects in the components that underlie the capacity of the immune system to perceive cell death as immunogenic negatively influence disease outcome among cancer patients treated with ICD inducers. Thus, ICD has profound clinical and therapeutic implications. Unfortunately, the gold-standard approach to detect ICD relies on vaccination experiments involving immunocompetent murine models and syngeneic cancer cells, an approach that is incompatible with large screening campaigns. Here, we outline strategies conceived to detect surrogate markers of ICD in vitro and to screen large chemical libraries for putative ICD inducers, based on a high-content, high-throughput platform that we recently developed. Such a platform allows for the detection of multiple DAMPs, like cell surface-exposed calreticulin, extracellular ATP and high mobility group box 1 (HMGB1), and/or the processes that underlie their emission, such as endoplasmic reticulum stress, autophagy and necrotic plasma membrane permeabilization. We surmise that this technology will facilitate the development of next-generation anticancer regimens, which kill malignant cells and simultaneously convert them into a cancer-specific therapeutic vaccine.Kepp, Oliver; Senovilla, Laura; Vitale, Ilio; Vacchelli, Erika; Adjemian, Sandy; Agostinis, Patrizia; Apetoh, Lionel; Aranda, Fernando; Barnaba, Vincenzo; Bloy, Norma; Bracci, Laura; Breckpot, Karine; Brough, David; Buqué, Aitziber; Castro, Maria G; Cirone, Mara; Colombo, Maria I; Cremer, Isabelle; Demaria, Sandra; Dini, Luciana; Eliopoulos, Aristides G; Faggioni, Alberto; Formenti, Silvia C; Fučíková, Jitka; Gabriele, Lucia; Gaipl, Udo S; Galon, Jérôme; Garg, Abhishek; Ghiringhelli, François; Giese, Nathalia A; Guo, Zong Sheng; Hemminki, Akseli; Herrmann, Martin; Hodge, James W; Holdenrieder, Stefan; Honeychurch, Jamie; Hu, Hong-Min; Huang, Xing; Illidge, Tim M; Kono, Koji; Korbelik, Mladen; Krysko, Dmitri V; Loi, Sherene; Lowenstein, Pedro R; Lugli, Enrico; Ma, Yuting; Madeo, Frank; Manfredi, Angelo A; Martins, Isabelle; Mavilio, Domenico; Menger, Laurie; Merendino, Nicolò; Michaud, Michael; Mignot, Gregoire; Mossman, Karen L; Multhoff, Gabriele; Oehler, Rudolf; Palombo, Fabio; Panaretakis, Theocharis; Pol, Jonathan; Proietti, Enrico; Ricci, Jean-Ehrland; Riganti, Chiara; Rovere-Querini, Patrizia; Rubartelli, Anna; Sistigu, Antonella; Smyth, Mark J; Sonnemann, Juergen; Spisek, Radek; Stagg, John; Sukkurwala, Abdul Qader; Tartour, Eric; Thorburn, Andrew; Thorne, Stephen H; Vandenabeele, Peter; Velotti, Francesca; Workenhe, Samuel T; Yang, Haining; Zong, Wei-Xing; Zitvogel, Laurence; Kroemer, Guido; Galluzzi, LorenzoKepp, Oliver; Senovilla, Laura; Vitale, Ilio; Vacchelli, Erika; Adjemian, Sandy; Agostinis, Patrizia; Apetoh, Lionel; Aranda, Fernando; Barnaba, Vincenzo; Bloy, Norma; Bracci, Laura; Breckpot, Karine; Brough, David; Buqué, Aitziber; Castro, Maria G; Cirone, Mara; Colombo, Maria I; Cremer, Isabelle; Demaria, Sandra; Dini, Luciana; Eliopoulos, Aristides G; Faggioni, Alberto; Formenti, Silvia C; Fučíková, Jitka; Gabriele, Lucia; Gaipl, Udo S; Galon, Jérôme; Garg, Abhishek; Ghiringhelli, François; Giese, Nathalia A; Guo, Zong Sheng; Hemminki, Akseli; Herrmann, Martin; Hodge, James W; Holdenrieder, Stefan; Honeychurch, Jamie; Hu, Hong Min; Huang, Xing; Illidge, Tim M; Kono, Koji; Korbelik, Mladen; Krysko, Dmitri V; Loi, Sherene; Lowenstein, Pedro R; Lugli, Enrico; Ma, Yuting; Madeo, Frank; Manfredi, Angelo A; Martins, Isabelle; Mavilio, Domenico; Menger, Laurie; Merendino, Nicolò; Michaud, Michael; Mignot, Gregoire; Mossman, Karen L; Multhoff, Gabriele; Oehler, Rudolf; Palombo, Fabio; Panaretakis, Theocharis; Pol, Jonathan; Proietti, Enrico; Ricci, Jean Ehrland; Riganti, Chiara; Rovere Querini, Patrizia; Rubartelli, Anna; Sistigu, Antonella; Smyth, Mark J; Sonnemann, Juergen; Spisek, Radek; Stagg, John; Sukkurwala, Abdul Qader; Tartour, Eric; Thorburn, Andrew; Thorne, Stephen H; Vandenabeele, Peter; Velotti, Francesca; Workenhe, Samuel T; Yang, Haining; Zong, Wei Xing; Zitvogel, Laurence; Kroemer, Guido; Galluzzi, Lorenz

Treatment with the anti-CD20 antibody (B1) and irradiation result in synergistic cytotoxicity that is dependent on MAPK activation

Radioimmunotherapy using radiolabeled anti-CD20 antibodies (mAb) is an effective new treatment in non-Hodgkin lymphoma with high response rates. However, the molecular mechanisms behind these impressive clinical responses are poorly understood. To elucidate these mechanisms we studied the signaling events evoked in a panel of lymphoma cell lines following treatment with anti-CD20 mAb alone or in combination with irradiation. In all three lymphoma cell-lines tested a synergistic cytotoxic effect was observed when the anti-CD20 mAb B1 was combined with irradiation. The additive effect seen with B1 mAb and radiation was not observed with Rituximab and could be reversed with MEK inhibitors U0126 and PD98059 as well as siRNA targeting MEK1 or 2. Moreover, addition of U0126 reversed the decrease in clonogenic survival triggered by treatment with B1 and irradiation. To further probe the mechanism of this synergistic cell death we used cell lines over-expressing BCL2 or crmA, to block mitochondrial and death receptor pathways, respectively. Although BCL2 and crmA over-expression mediated protection against radiation alone, it had no impact on the increased cytotoxicity induced by B1+irradiation. Morphological studies revealed gross vacuolization of the cytoplasm, yet relatively well preserved nuclei in cells treated with B1+irradiation. Taken together our data indicate that activation of the MAPK cascade is an important factor that contributes to the synergistic effect of anti-CD20 (B1) antibody and irradiation and provides important new insights into how this treatment may work in the clinic