VOLUME
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2015
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Adoptive T-Cell Therapy Is a Promising Salvage Approach for Advanced or Recurrent Metastatic Cervical Cancer Emese Zsiros, Takemasa Tsuji, and Kunle Odunsi, Center for Immunotherapy, Roswell Park Cancer Institute, Buffalo, NY See accompanying article on page 1543
Cervical cancer is one of the leading causes of cancer-related death in women worldwide. Although the disease is frequently curable in early stages with surgery alone or surgery and adjuvant chemoradiotherapy, there are no effective therapies for advanced or recurrent metastatic cervical cancers. Recently, antiangiogenic therapy using bevacizumab, a humanized monoclonal antibody against vascular endothelial growth factor, has demonstrated clinical efficacy in combination with paclitaxel and cisplatin, leading to its regulatory approval for advanced and recurrent cervical cancer.1 Although this represents some progress in the treatment of patients with cervical cancer, the addition of bevacizumab is unlikely to translate into durable cure for the majority of these patients. Thus, there is an enormous clinical need to develop novel effective strategies, such as immunotherapy, for this patient population. Persistent infection with specific high-risk human papillomavirus (HR-HPV; eg, HPV-16, HPV-18, HPV-31, HPV-33, and HPV45) has been identified as an essential factor in the pathogenesis of the majority of cervical cancers, with detectable HR-HPV in up to 99.7% of carcinoma specimens.2 Similar to nononcogenic viruses, such as influenza and cytomegalovirus, HPV is highly immunogenic and elicits immune responses in humans. Although prophylactic HPV vaccines targeting L1 and L2 virion structural proteins have demonstrated efficacy in preventing HPV-related cancers, therapeutic vaccines targeting E6 and E7 oncoproteins have not produced significant clinical responses. The barrier to establishing an effective therapeutic HPV vaccine against cervical cancer has been a lack of clinical response to any of the existing regimens.3 This is probably because of the relatively low magnitude of vaccine-induced immune responses, and tumormediated immune suppression. In the article that accompanies this editorial, Stevanovi´c et al4 present a promising adoptive T-cell therapy (ACT) approach by which patients with recurrent, chemotherapyresistant metastatic cervical cancer were treated with a single infusion of ex vivo– expanded tumor-infiltrating T cells. In contrast with tumor vaccination strategies, ACT allows for more rigorous control over the magnitude of the targeted response by appropriate in vitro manipulation and selection of the T cells used for therapy. Tumor-reactive effector cells of a desired specificity and phenotype can be identified in vitro, exposed to cytokines and immunomodulators that influence differentiation during priming, expanded Journal of Clinical Oncology, Vol 33, No 14 (May 10), 2015: pp 1521-1522
to large numbers, and produce frequencies of antigen-specific T cells in the peripheral blood that are more than 10-fold greater than those possible by current vaccine regimens alone. Initial results that demonstrated the potential of T-cell immunotherapy to eradicate solid tumors came from the National Cancer Institute in studies of adoptive transfer of in vitro–selected tumor-infiltrating lymphocytes (TILs).5,6 In a pioneering clinical trial in 13 patients with melanoma, adoptive transfer of ex vivo–amplified autologous tumor-infiltrating T cells induced objective clinical responses in six patients and mixed responses in four additional patients.5 However, results in solid tumors and epithelial malignancies are still limited, mainly because of the technical challenges in obtaining enough tumor specimens and isolating and expanding tumor-reactive T cells. In the protocol used by Stevanovi´c et al,4 the T cells were obtained from tumor specimens that required a surgical excision of 1 cm3 tumor in each patient, expanded with interleukin-2 (IL-2), and used for ACT. T-cell products were tested for reactivity against HPV-16 or HPV-18 E6 and E7 oncoproteins. T-cell infusion was preceded by lymphodepleting chemotherapy and was followed by the administration of multiple doses of aldesleukin. In the study, nine patients were treated using this protocol, and three patients showed objective tumor response. Of these, two patients (both young, age 36 years, who were experiencing progression during receipt of palliative treatment) had a durable complete clinical response that lasted more than a year. Although the numbers are small, these results are impressive and suggest that this highly personalized therapeutic modality warrants further investigation. Importantly, the treatment was safe and well tolerated, but, as expected, the major toxicity resulted from the preconditioning lymphodepleting chemotherapy before the infusion. It is currently well recognized that the preconditioning step is critical for achieving a high level of T-cell engraftment because it creates space for the adoptively transferred T cells to populate in the absence of host-cell competition.7,8 Although the number of patients was too small to draw a general conclusion, the results clearly showed a correlation between HPV reactivity of the infused T-cell products and objective clinical responses. First, only when the infusion product had reactivity against the HPV E6 and E7 peptides did the patient show objective clinical response. Second, in patients with objective responses, HPV-specific T © 2015 by American Society of Clinical Oncology
Downloaded from jco.ascopubs.org on October 22, 2015. For personal use only. No other uses without permission. Copyright © 2015 American Society of Clinical Oncology. All rights reserved.
1521
Editorial
cells were shown to persist in peripheral blood for months after the infusion. These results strongly suggest that the clinical response was mediated by the expanded HPV-reactive T cells. HPV-derived antigens, including E6 and E7 oncoproteins, are considered to be among the ideal tumor-rejection antigens because of the absence of the selftolerance mechanism. However, given that cervical cancer cells express other immunogenic tumor antigens such as NY-ESO-1 and MAGE-A family members, along with mutational neoantigens,9,10 it is still possible that HPV reactivity is a sensitive biomarker for the overall tumor antigen–specificity of the cell products. In that regard, the presence of HPV-specific T cells in the expanded T-cell population is associated with the expansion of other tumor-reactive T cells that are specific against an array of immunogenic tumor antigens expressed in the tumor. Therefore, it is unclear whether HPV-specific T cells were solely responsible for the tumor eradication or if other expanded tumor antigen–specific T cells could have contributed to this remarkable clinical response. Addressing this question may require an ACT trial using HPV-monospecific T-cell products. Unfortunately, methods of isolating and manufacturing TILs are labor intensive and only successful in a subset of patients (approximately 30% to 40%).11,12 An attractive strategy to redirect a patient’s own T cells to a specific tumor-associated antigen (TAA) is to genetically alter the cells to express a TAA-specific T-cell receptor (TCR) or chimeric antigen receptor (CAR) gene.13 This strategy endows the T cells with the specificity of the donor TCR and/or TAA. If HPV E6- or E7-specific T cells alone mediate the objective clinical responses found in this study, HPV-specific TCR genes from these T cells will be promising gene products for the development of efficient ACT for HPV-related cancers. The results of this trial indicate that the frequency of HPVreactive T cells in the peripheral blood 1 month after the treatment is associated with clinical response. Although the HPV-reactive T cells in this study were isolated from tumor biopsies, it is still unclear whether expanded HPV-reactive T cells efficiently trafficked into the tumor microenvironment after ACT. In this study, no post-treatment biopsies were obtained in any of the patients, but, interestingly, the analysis of tumor-infiltrating CD3⫹, CD4⫹, and CD8⫹ cells in the excised pretreatment samples did not reveal statistically significant correlations with response to treatment. The authors explained this by noting that TILs were not isolated directly from the tumors but rather expanded from tumor fragments using IL-2– containing culture media. However, it would be fundamental to investigate the immune composition of post-treatment samples in future clinical trials to further understand if ACT led to an increased number of functional effector T cells in the tumor microenvironment. This study provided strong evidence that T cells in some (but probably not all) cervical tumors can mediate complete responses when they are ex vivo– expanded and adoptively transferred. The major obstacle to ACT and other forms of immunotherapy is the immunosuppressive environment of tumors. These factors include
regulatory T cells and myeloid-derived suppressor cells, as well as IL-10, transforming growth factor , vascular endothelial growth factor, prostaglandin E2, and programmed death-ligand 1, and facilitate tumor immune evasion. It is likely that concomitantly counteracting these tolerogenic mechanisms may be required to further enhance the efficacy of ACT in future approaches. Targeting HPV E6 and E7 oncoproteins with ACT not only has relevance in cervical cancer, but could be an effective treatment for other HPV-relatedcancerssuchasthoseoftheoropharynx,vulva,vagina,penis, and anus. Although the number of patients in this clinical trial is small, the results are promising and suggest that ACT can mediate complete and durable regression of epithelial malignancies. AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
Disclosures provided by the authors are available with this article at www.jco.org. AUTHOR CONTRIBUTIONS
Manuscript writing: All authors Final approval of manuscript: All authors REFERENCES 1. Tewari KS, Sill MW, Long HJ 3rd, et al: Improved survival with bevacizumab in advanced cervical cancer. N Engl J Med 370:734-743, 2014 2. Walboomers JM, Jacobs MV, Manos MM, et al: Human papillomavirus is a necessary cause of invasive cervical cancer worldwide. J Pathol 189:12-19, 1999 3. Stern PL, van der Burg SH, Hampson IN, et al: Therapy of human papillomavirus-related disease. Vaccine 30:F71-F82, 2012 (suppl 5) 4. Stevanovic´ S, Draper LM, Langhan MM, et al: Complete regression of metastatic cervical cancer after treatment with human papillomavirus–targeted tumor-infiltrating T cells. J Clin Oncol 33:1543-1550, 2015 5. Dudley ME, Wunderlich JR, Robbins PF, et al: Cancer regression and autoimmunity in patients after clonal repopulation with antitumor lymphocytes. Science 298:850-854, 2002 6. Dudley ME, Wunderlich JR, Yang JC, et al: Adoptive cell transfer therapy following non-myeloablative but lymphodepleting chemotherapy for the treatment of patients with refractory metastatic melanoma. J Clin Oncol 23:23462357, 2005 7. Cho HI, Reyes-Vargas E, Delgado JC, et al: A potent vaccination strategy that circumvents lymphodepletion for effective antitumor adoptive T-cell therapy. Cancer Res 72:1986-1995, 2012 8. Gilham DE: Effective adoptive T-cell therapy for cancer in the absence of host lymphodepletion. Immunotherapy 3:177-179, 2011 9. Napoletano C, Bellati F, Tarquini E, et al: MAGE-A and NY-ESO-1 expression in cervical cancer: Prognostic factors and effects of chemotherapy. Am J Obstet Gynecol 198:99.e1-e7, 2008 10. Lawrence MS, Stojanov P, Polak P, et al: Mutational heterogeneity in cancer and the search for new cancer-associated genes. Nature 499:214-218, 2013 11. Dudley ME, Wunderlich JR, Shelton TE, et al: Generation of tumorinfiltrating lymphocyte cultures for use in adoptive transfer therapy for melanoma patients. J Immunother 26:332-342, 2003 12. Dudley ME, Yang JC, Sherry R, et al: Adoptive cell therapy for patients with metastatic melanoma: Evaluation of intensive myeloablative chemoradiation preparative regimens. J Clin Oncol 26:5233-5239, 2008 13. Park TS, Rosenberg SA, Morgan RA: Treating cancer with genetically engineered T cells. Trends Biotechnol 29:550-557, 2011
DOI: 10.1200/JCO.2014.60.6566; published online ahead of print at www.jco.org on April 6, 2015
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1522
© 2015 by American Society of Clinical Oncology
JOURNAL OF CLINICAL ONCOLOGY
Downloaded from jco.ascopubs.org on October 22, 2015. For personal use only. No other uses without permission. Copyright © 2015 American Society of Clinical Oncology. All rights reserved.
Editorial
AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
Adoptive T-Cell Therapy Is a Promising Salvage Approach for Advanced or Recurrent Metastatic Cervical Cancer The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. I ⫽ Immediate Family Member, Inst ⫽ My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO’s conflict of interest policy, please refer to www.asco.org/rwc or jco.ascopubs.org/site/ifc. Emese Zsiros No relationship to disclose
Kunle Odunsi No relationship to disclose
Takemasa Tsuji No relationship to disclose
www.jco.org
© 2015 by American Society of Clinical Oncology
Downloaded from jco.ascopubs.org on October 22, 2015. For personal use only. No other uses without permission. Copyright © 2015 American Society of Clinical Oncology. All rights reserved.
Editorial
Acknowledgment K.O. is supported by the National Cancer Institute of the National Institutes of Health under Award Number P50CA159981, and T.T. is supported by a 2014-2015 Developmental Funds award from the Roswell Park Alliance Foundation and the Ovarian Cancer Research Fund under Grant No. 327679.
© 2015 by American Society of Clinical Oncology
JOURNAL OF CLINICAL ONCOLOGY
Downloaded from jco.ascopubs.org on October 22, 2015. For personal use only. No other uses without permission. Copyright © 2015 American Society of Clinical Oncology. All rights reserved.
33
䡠
NUMBER
14
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MAY
10
2015
JOURNAL OF CLINICAL ONCOLOGY
E
D
I
T
O
R
I
A
L
Adoptive T-Cell Therapy Is a Promising Salvage Approach for Advanced or Recurrent Metastatic Cervical Cancer Emese Zsiros, Takemasa Tsuji, and Kunle Odunsi, Center for Immunotherapy, Roswell Park Cancer Institute, Buffalo, NY See accompanying article on page 1543
Cervical cancer is one of the leading causes of cancer-related death in women worldwide. Although the disease is frequently curable in early stages with surgery alone or surgery and adjuvant chemoradiotherapy, there are no effective therapies for advanced or recurrent metastatic cervical cancers. Recently, antiangiogenic therapy using bevacizumab, a humanized monoclonal antibody against vascular endothelial growth factor, has demonstrated clinical efficacy in combination with paclitaxel and cisplatin, leading to its regulatory approval for advanced and recurrent cervical cancer.1 Although this represents some progress in the treatment of patients with cervical cancer, the addition of bevacizumab is unlikely to translate into durable cure for the majority of these patients. Thus, there is an enormous clinical need to develop novel effective strategies, such as immunotherapy, for this patient population. Persistent infection with specific high-risk human papillomavirus (HR-HPV; eg, HPV-16, HPV-18, HPV-31, HPV-33, and HPV45) has been identified as an essential factor in the pathogenesis of the majority of cervical cancers, with detectable HR-HPV in up to 99.7% of carcinoma specimens.2 Similar to nononcogenic viruses, such as influenza and cytomegalovirus, HPV is highly immunogenic and elicits immune responses in humans. Although prophylactic HPV vaccines targeting L1 and L2 virion structural proteins have demonstrated efficacy in preventing HPV-related cancers, therapeutic vaccines targeting E6 and E7 oncoproteins have not produced significant clinical responses. The barrier to establishing an effective therapeutic HPV vaccine against cervical cancer has been a lack of clinical response to any of the existing regimens.3 This is probably because of the relatively low magnitude of vaccine-induced immune responses, and tumormediated immune suppression. In the article that accompanies this editorial, Stevanovi´c et al4 present a promising adoptive T-cell therapy (ACT) approach by which patients with recurrent, chemotherapyresistant metastatic cervical cancer were treated with a single infusion of ex vivo– expanded tumor-infiltrating T cells. In contrast with tumor vaccination strategies, ACT allows for more rigorous control over the magnitude of the targeted response by appropriate in vitro manipulation and selection of the T cells used for therapy. Tumor-reactive effector cells of a desired specificity and phenotype can be identified in vitro, exposed to cytokines and immunomodulators that influence differentiation during priming, expanded Journal of Clinical Oncology, Vol 33, No 14 (May 10), 2015: pp 1521-1522
to large numbers, and produce frequencies of antigen-specific T cells in the peripheral blood that are more than 10-fold greater than those possible by current vaccine regimens alone. Initial results that demonstrated the potential of T-cell immunotherapy to eradicate solid tumors came from the National Cancer Institute in studies of adoptive transfer of in vitro–selected tumor-infiltrating lymphocytes (TILs).5,6 In a pioneering clinical trial in 13 patients with melanoma, adoptive transfer of ex vivo–amplified autologous tumor-infiltrating T cells induced objective clinical responses in six patients and mixed responses in four additional patients.5 However, results in solid tumors and epithelial malignancies are still limited, mainly because of the technical challenges in obtaining enough tumor specimens and isolating and expanding tumor-reactive T cells. In the protocol used by Stevanovi´c et al,4 the T cells were obtained from tumor specimens that required a surgical excision of 1 cm3 tumor in each patient, expanded with interleukin-2 (IL-2), and used for ACT. T-cell products were tested for reactivity against HPV-16 or HPV-18 E6 and E7 oncoproteins. T-cell infusion was preceded by lymphodepleting chemotherapy and was followed by the administration of multiple doses of aldesleukin. In the study, nine patients were treated using this protocol, and three patients showed objective tumor response. Of these, two patients (both young, age 36 years, who were experiencing progression during receipt of palliative treatment) had a durable complete clinical response that lasted more than a year. Although the numbers are small, these results are impressive and suggest that this highly personalized therapeutic modality warrants further investigation. Importantly, the treatment was safe and well tolerated, but, as expected, the major toxicity resulted from the preconditioning lymphodepleting chemotherapy before the infusion. It is currently well recognized that the preconditioning step is critical for achieving a high level of T-cell engraftment because it creates space for the adoptively transferred T cells to populate in the absence of host-cell competition.7,8 Although the number of patients was too small to draw a general conclusion, the results clearly showed a correlation between HPV reactivity of the infused T-cell products and objective clinical responses. First, only when the infusion product had reactivity against the HPV E6 and E7 peptides did the patient show objective clinical response. Second, in patients with objective responses, HPV-specific T © 2015 by American Society of Clinical Oncology
Downloaded from jco.ascopubs.org on October 22, 2015. For personal use only. No other uses without permission. Copyright © 2015 American Society of Clinical Oncology. All rights reserved.
1521
Editorial
cells were shown to persist in peripheral blood for months after the infusion. These results strongly suggest that the clinical response was mediated by the expanded HPV-reactive T cells. HPV-derived antigens, including E6 and E7 oncoproteins, are considered to be among the ideal tumor-rejection antigens because of the absence of the selftolerance mechanism. However, given that cervical cancer cells express other immunogenic tumor antigens such as NY-ESO-1 and MAGE-A family members, along with mutational neoantigens,9,10 it is still possible that HPV reactivity is a sensitive biomarker for the overall tumor antigen–specificity of the cell products. In that regard, the presence of HPV-specific T cells in the expanded T-cell population is associated with the expansion of other tumor-reactive T cells that are specific against an array of immunogenic tumor antigens expressed in the tumor. Therefore, it is unclear whether HPV-specific T cells were solely responsible for the tumor eradication or if other expanded tumor antigen–specific T cells could have contributed to this remarkable clinical response. Addressing this question may require an ACT trial using HPV-monospecific T-cell products. Unfortunately, methods of isolating and manufacturing TILs are labor intensive and only successful in a subset of patients (approximately 30% to 40%).11,12 An attractive strategy to redirect a patient’s own T cells to a specific tumor-associated antigen (TAA) is to genetically alter the cells to express a TAA-specific T-cell receptor (TCR) or chimeric antigen receptor (CAR) gene.13 This strategy endows the T cells with the specificity of the donor TCR and/or TAA. If HPV E6- or E7-specific T cells alone mediate the objective clinical responses found in this study, HPV-specific TCR genes from these T cells will be promising gene products for the development of efficient ACT for HPV-related cancers. The results of this trial indicate that the frequency of HPVreactive T cells in the peripheral blood 1 month after the treatment is associated with clinical response. Although the HPV-reactive T cells in this study were isolated from tumor biopsies, it is still unclear whether expanded HPV-reactive T cells efficiently trafficked into the tumor microenvironment after ACT. In this study, no post-treatment biopsies were obtained in any of the patients, but, interestingly, the analysis of tumor-infiltrating CD3⫹, CD4⫹, and CD8⫹ cells in the excised pretreatment samples did not reveal statistically significant correlations with response to treatment. The authors explained this by noting that TILs were not isolated directly from the tumors but rather expanded from tumor fragments using IL-2– containing culture media. However, it would be fundamental to investigate the immune composition of post-treatment samples in future clinical trials to further understand if ACT led to an increased number of functional effector T cells in the tumor microenvironment. This study provided strong evidence that T cells in some (but probably not all) cervical tumors can mediate complete responses when they are ex vivo– expanded and adoptively transferred. The major obstacle to ACT and other forms of immunotherapy is the immunosuppressive environment of tumors. These factors include
regulatory T cells and myeloid-derived suppressor cells, as well as IL-10, transforming growth factor , vascular endothelial growth factor, prostaglandin E2, and programmed death-ligand 1, and facilitate tumor immune evasion. It is likely that concomitantly counteracting these tolerogenic mechanisms may be required to further enhance the efficacy of ACT in future approaches. Targeting HPV E6 and E7 oncoproteins with ACT not only has relevance in cervical cancer, but could be an effective treatment for other HPV-relatedcancerssuchasthoseoftheoropharynx,vulva,vagina,penis, and anus. Although the number of patients in this clinical trial is small, the results are promising and suggest that ACT can mediate complete and durable regression of epithelial malignancies. AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
Disclosures provided by the authors are available with this article at www.jco.org. AUTHOR CONTRIBUTIONS
Manuscript writing: All authors Final approval of manuscript: All authors REFERENCES 1. Tewari KS, Sill MW, Long HJ 3rd, et al: Improved survival with bevacizumab in advanced cervical cancer. N Engl J Med 370:734-743, 2014 2. Walboomers JM, Jacobs MV, Manos MM, et al: Human papillomavirus is a necessary cause of invasive cervical cancer worldwide. J Pathol 189:12-19, 1999 3. Stern PL, van der Burg SH, Hampson IN, et al: Therapy of human papillomavirus-related disease. Vaccine 30:F71-F82, 2012 (suppl 5) 4. Stevanovic´ S, Draper LM, Langhan MM, et al: Complete regression of metastatic cervical cancer after treatment with human papillomavirus–targeted tumor-infiltrating T cells. J Clin Oncol 33:1543-1550, 2015 5. Dudley ME, Wunderlich JR, Robbins PF, et al: Cancer regression and autoimmunity in patients after clonal repopulation with antitumor lymphocytes. Science 298:850-854, 2002 6. Dudley ME, Wunderlich JR, Yang JC, et al: Adoptive cell transfer therapy following non-myeloablative but lymphodepleting chemotherapy for the treatment of patients with refractory metastatic melanoma. J Clin Oncol 23:23462357, 2005 7. Cho HI, Reyes-Vargas E, Delgado JC, et al: A potent vaccination strategy that circumvents lymphodepletion for effective antitumor adoptive T-cell therapy. Cancer Res 72:1986-1995, 2012 8. Gilham DE: Effective adoptive T-cell therapy for cancer in the absence of host lymphodepletion. Immunotherapy 3:177-179, 2011 9. Napoletano C, Bellati F, Tarquini E, et al: MAGE-A and NY-ESO-1 expression in cervical cancer: Prognostic factors and effects of chemotherapy. Am J Obstet Gynecol 198:99.e1-e7, 2008 10. Lawrence MS, Stojanov P, Polak P, et al: Mutational heterogeneity in cancer and the search for new cancer-associated genes. Nature 499:214-218, 2013 11. Dudley ME, Wunderlich JR, Shelton TE, et al: Generation of tumorinfiltrating lymphocyte cultures for use in adoptive transfer therapy for melanoma patients. J Immunother 26:332-342, 2003 12. Dudley ME, Yang JC, Sherry R, et al: Adoptive cell therapy for patients with metastatic melanoma: Evaluation of intensive myeloablative chemoradiation preparative regimens. J Clin Oncol 26:5233-5239, 2008 13. Park TS, Rosenberg SA, Morgan RA: Treating cancer with genetically engineered T cells. Trends Biotechnol 29:550-557, 2011
DOI: 10.1200/JCO.2014.60.6566; published online ahead of print at www.jco.org on April 6, 2015
■ ■ ■
1522
© 2015 by American Society of Clinical Oncology
JOURNAL OF CLINICAL ONCOLOGY
Downloaded from jco.ascopubs.org on October 22, 2015. For personal use only. No other uses without permission. Copyright © 2015 American Society of Clinical Oncology. All rights reserved.
Editorial
AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
Adoptive T-Cell Therapy Is a Promising Salvage Approach for Advanced or Recurrent Metastatic Cervical Cancer The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. I ⫽ Immediate Family Member, Inst ⫽ My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO’s conflict of interest policy, please refer to www.asco.org/rwc or jco.ascopubs.org/site/ifc. Emese Zsiros No relationship to disclose
Kunle Odunsi No relationship to disclose
Takemasa Tsuji No relationship to disclose
www.jco.org
© 2015 by American Society of Clinical Oncology
Downloaded from jco.ascopubs.org on October 22, 2015. For personal use only. No other uses without permission. Copyright © 2015 American Society of Clinical Oncology. All rights reserved.
Editorial
Acknowledgment K.O. is supported by the National Cancer Institute of the National Institutes of Health under Award Number P50CA159981, and T.T. is supported by a 2014-2015 Developmental Funds award from the Roswell Park Alliance Foundation and the Ovarian Cancer Research Fund under Grant No. 327679.
© 2015 by American Society of Clinical Oncology
JOURNAL OF CLINICAL ONCOLOGY
Downloaded from jco.ascopubs.org on October 22, 2015. For personal use only. No other uses without permission. Copyright © 2015 American Society of Clinical Oncology. All rights reserved.
