- Email: [email protected]
An Intravenous Stimulus Package for Oncolytic Virotherapy
© The American Society of Gene & Cell Therapy
commentary References 1.
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Kochenderfer, JN, Wilson, WH, Janik, JE, Dudley, ME, Stetler-Stevenson, M, Feldman, SA et al. (2010). Eradication of B-lineage cells and regression of lymphoma in a patient treated with autologous T cells genetically engineered to recognize CD19. Blood 116: 4099–4102. Porter, DL, Levine, BL, Kalos, M, Bagg, A and June, CH (2011). Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia. N Engl J Med 365: 725–733. Kalos, M, Levine, BL, Porter, DL, Katz, S, Grupp, SA, Bagg, A et al. (2011). T cells with chimeric antigen receptors have potent antitumor effects and can establish memory in patients with advanced leukemia. Sci Transl Med 3: 95ra73. Brentjens, RJ, Rivière, I, Park, JH, Davila, ML, Wang, X, Stefanski, J et al. (2011). Safety and persistence of adoptively transferred autologous CD19-targeted T cells in patients with relapsed or chemotherapy refractory B-cell leukemias. Blood; e-pub ahead of print 17 August 2011. Dudley, ME, Wunderlich, JR, Robbins, PF, Yang, JC, Hwu, P, Schwartzentruber, DJ et al. (2002). Cancer regression and autoimmunity in patients after clonal repopulation with anti-tumor lymphocytes. Science 298: 850–854. Dudley, ME, Yang, JC, Sherry, R, Hughes, MS, Royal, R, Kammula, U et al. (2008). Adoptive cell therapy for patients with metastatic melanoma: evaluation of intensive myeloablative chemoradiation preparative regimens. J Clin Oncol 26: 5233–5239. Rosenberg, SA, Yang, JC, Sherry, RM, Kammula, US, Hughes, MS, Phan, GQ et al. (2011). Durable complete responses in heavily pretreated patients with metastatic melanoma using T-cell transfer immunotherapy. Clin Cancer Res 17: 4550–4557. Rosenberg, SA, Restifo, NP, Yang, JC, Morgan, RA and Dudley, ME (2008). Adoptive cell transfer: a clinical path to effective cancer immunotherapy. Nat Rev Cancer 8: 299–308. Rosenberg, SA (2011). Cell transfer immunotherapy for metastatic solid cancer—what clinicians need to know. Nat Rev Clin Oncol; e-pub ahead of print 2 August 2011. Morgan, RA, Dudley, ME, Wunderlich, JR, Hughes, MS, Yang, JC, Sherry, RM et al. (2006). Cancer regression in patients after transfer of genetically engineered lymphocytes. Science 314: 126–129. Johnson, LA, Morgan, RA, Dudley, ME, Cassard, L, Yang, JC, Hughes, MS et al. (2009). Gene therapy with human and mouse T-cell receptors mediates cancer regression and targets normal tissues expressing cognate antigen. Blood 114: 535–546. Morgan, RA, Dudley, ME and Rosenberg, SA (2010). Adoptive cell therapy: genetic modification to redirect effector cell specificity. Cancer J 16: 336–341. Gross, G, Waks, T and Eshhar Z (1989). Expression of immunoglobulin-T-cell receptor chimeric molecules as functional receptors with antibody-type specificity. Proc Natl Acad Sci USA 86: 10024–10028. Hwu, P, Yang, JC, Cowherd, R, Treisman, J, Shafer, GE and Rosenberg, SA (1995). In vivo antitumor activity of T-cells redirected with chimeric antibody/T-cell receptor genes. Cancer Res 55: 3369–3373. Kershaw, MH, Westwood, JA, Parker, LL, Wang, G, Eshhar, Z, Mavroukakis, SA et al. (2006). A phase I study on adoptive immunotherapy using gene-modified T cells for ovarian cancer. Clin Cancer Res 12: 6106–6115. Lamers, CHJ, Sleiffer, S, Vulto, AG, Kruit, WH, Kliffen, M, Debets, R et al. (2006). Treatment of metastatic renal cell carcinoma with autologous T-lymphocytes genetically retargeted against carbonic anhydrase IX: first clinical experience. J Clin Oncol 24: e20–e22. Pule, MA, Savoldo, B, Myers, GD, Rossig, C, Russell, HV, Dotti, G et al. (2008). Virus-specific T cells engineered to coexpress tumor-specific receptors: persistence and antitumor activity in individuals with neuroblastoma. Nat Med 14: 1264–1270. Simpson, AJ, Caballero, OL, Jungbluth, A, Chen, YT and Old, LJ (2005). Cancer/testis antigens, gametogenesis and cancer. Nat Rev Cancer 5: 615–625. Robbins, PF, Morgan, RA, Feldman, SA, Yang, JC, Sherry, RM, Dudley, ME et al. (2011). Tumor regression in patients with metastatic synovial sarcoma and melanoma using genetically engineered lymphocytes reactive with NY-ESO-1. J Clin Oncol 29: 917–924. Chinnasamy, N, Wargo, JA, Yu, Z, Rao, M, Frankel, TL, Riley, JP et al. (2011). A TCR targeting the HLA-A*01restricted epitope of MAGE-A3 recognizes multiple epitopes of the MAGE-A antigen superfamily in several types of cancer. J Immunol 186: 685–696.
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21. Parkhurst, MR, Yang, JC, Langan, RC, Dudley, ME, Nathan, DA, Feldman, SA et al. (2011). T cells targeting carcinoembryonic antigen can mediate regression of metastatic colorectal cancer but induce severe transient colitis. Mol Ther 19: 620–626. 22. Morgan, RA, Yang, JC, Kitano, M, Dudley, ME, Laurencot, CM and Rosenberg, SA (2010). Case report of a serious adverse event following the administration of T cells transduced with a chimeric antigen receptor recognizing ERBB2. Mol Ther 18: 843–851. 23. Brentjens, RJ, Latouche, JB, Santos, E, Marti, F, Gong, MC, Lyddane, C et al. (2003). Eradication of systemic B-cell tumors by genetically targeted human T lymphocytes co-stimulated by CD80 and interleukin-15. Nat Med 9: 279–286. 24. Cooper, LJ, Topp, MS, Serrano, LM, Gonzalez, S, Chang, WC, Naranjo, A et al. (2003). T-cell clones can be rendered specific for CD19: toward the selective augmentation of the graft-versus-B lineage leukemia effect. Blood 101: 1637–1644. 25. Brentjens, RJ, Santos, E, Nikhamin, Y, Yeh, R, Matsushita, M, La Perle, K et al. (2007). Genetically targeted T cells eradicate systemic acute lymphoblastic leukemia xenografts. Clin Cancer Res 13: 5426–5435. 26. Cheadle, EJ, Hawkins, RE, Batha, H, O’Neill, AL, Dovedi, SJ and Gilham, DE (2010). Natural expression of the CD19 antigen impacts the long-term engraftment but not antitumor activity of CD19-specific engineered T cells. J Immunother 184: 1885–1896. 27. Imai, C, Mihara, K, Andreansky, M, Nicholson, IC, Pui, CH, Geiger, TL et al. (2004). Chimeric receptors with 4-1BB signaling capacity provoke potent cytotoxicity against acute lymphoblastic leukemia. Leukemia 18: 678–684. 28. Kowolik, CM, Topps, MS, Gonzalez, S, Pfeiffer, T, Olivares, S, Gonzalez, N et al. (2006). CD28 costimulation provided through a CD19-specific chimeric antigen receptor enhances in vivo persistence and antitumor efficacy of adoptively transferred T cells. Cancer Res 66: 10995–11004. 29. Milone, MC, Fish, JD, Carpenito, C, Carroll, RG, Binder, GK, Teachey, D et al. (2009). Chimeric receptors containing CD137 signal transduction domains mediate enhanced survival of T cells and increased antileukemic efficacy in vivo. Mol Ther 17: 1453–1464. 30. Rossig, C, Bär, A, Pscherer, S, Altvater, B, Pule, M, Rooney, CM et al. (2006). Target antigen expression on a professional antigen-presenting cell induces superior proliferative antitumor T-cell responses via chimeric T-cell receptors. J Immunother 29: 21–31. 31. Jensen, MC, Popplewell, L, Cooper, LJ, DiGiusto, D, Kalos, M, Ostberg, JR et al. (2010). Antitransgene
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rejection responses contribute to attenuated persistence of adoptively transferred CD20/CD19-specific chimeric antigen receptor redirected T cells in humans. Biol Blood Marrow Transplant 16: 1245–1256. Kochenderfer, JN, Feldman, SA, Zhao, Y, Xu, H, Black, MA, Morgan, RA et al. (2009). Construction and preclinical evaluation of an anti-CD19 chimeric antigen receptor. J Immunother 32: 689–702. Kochenderfer, JN, Yu, Z, Frasheri, D, Restifo, NP and Rosenberg, SA (2010). Adoptive transfer of syngeneic T cells transduced with a chimeric antigen receptor that recognizes murine CD19 can eradicate lymphoma and normal B cells. Blood 116: 3875–3886. Brentjens, R, Yeh, R, Bernal, Y, Riviere, I and Sadelain, M (2010). Treatment of chronic lymphocytic leukemia with genetically targeted autologous T cells: case report of an unforeseen adverse event in a phase 1 clinical trial. Mol Ther 18: 666–668. Savoldo, B, Ramos, CA, Liu, E, Mims, MP, Keating, MJ, Carrum, G et al. (2011). CD28 costimulation improves expansion and persistence of chimeric antigen receptormodified T cells in lymphoma patients. J Clin Invest 121: 1822–1826. Klebanoff, CA, Gattinoni, L, Palmer, DC, Muranski, P, Ji, Y, Hinrichs, CS et al. (2011). Determinants of successful CD8+ T-cell adoptive immunotherapy for large established tumors in mice. Clin Cancer Res 17: 5343–5352. Gattinoni, L, Powell, DJ, Rosenberg, SA and Restifo, NP (2006). Adoptive immunotherapy for cancer: building on success. Nat Rev Immunol 6: 383–393. Bonini, C, Brenner, MK, Heslop, HE and Morgan, RA (2011). Genetic modification of T cells. Biol Blood Marrow Transplant 17: S15–S20. Tey, S, Dotti, G, Rooney, CM, Heslop, HE and Brenner, MK (2007). Inducible caspase 9 suicide gene to improve the safety of allodepleted T cells after haploidentical stem cell transplantation. Biol Blood Marrow Transplant 13: 913–924. Liu, K and Rosenberg, SA (2001). Transduction of an interleukin-2 gene into human melanoma-reactive lymphocytes results in their continued growth in the absence of exogenous IL-2 and maintenance of specific antitumor activity. J Immunol 167: 6356–6365. Kerkar, SP, Muranski, P, Kaiser, A, Boni, A, SanchezPerez, L, Yu, Z et al. (2010). Tumor-specific CD8+ T cells expressing interleukin-12 eradicate established cancers in lymphodepleted hosts. Cancer Res 70: 6725–6734. Stephan, MT, Ponomarev, V, Brentjens, RJ, Chang, AH, Dobrenkov, KV, Heller, G et al. (2007). T cell–encoded CD80 and 4-1BBL induce auto- and transcostimulation, resulting in potent tumor rejection. Nat Med 13: 1440–1449.
An Intravenous Stimulus Package for Oncolytic Virotherapy Richard Vile1,2 and Alan Melcher2 doi:10.1038/mt.2011.217
A
recently published phase I clinical trial shows that an oncolytic
1 Departments of Molecular Medicine and Immunology, Mayo Clinic, Rochester, Minnesota, USA; 2Leeds Institute of Molecular Medicine and Cancer Research UK Clinical Centre, St. James’ University Hospital, Leeds, UK Correspondence: Richard Vile, Mayo Clinic, Guggenheim 18, 200 First Street SW, Rochester, Minnesota 55905, USA. E-mail: [email protected]
vaccinia virus, JX-594, can reach and infect tumors following a single intravenous infusion, despite the barriers to systemic virus spread.1 Direct evidence of virus localization in tumors, along with a portfolio of supportive data, suggests that virus can also replicate selectively in tumors. These data come extremely close to validating the basic principles underlying the development of replicating viruses for cancer therapy.2,3
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© The American Society of Gene & Cell Therapy
The impending collapse of the world’s financial apparatus4 is generally unnerving, but the most concerning aspect is the radically divergent solutions proposed by the politicians and economists whose job it is to pull us back from the precipice—should we spend our way out of recession or make deep cuts to balance the budget?5 Although the success, or otherwise, of oncolytic virotherapy (OV) may have rather less global significance to most people than the financial meltdown, to analysts monitoring the “futures” of novel cancer therapies, the debates surrounding OV appear to have become as contradictory, and bewilderingly polarized, as those addressing the current politico-economic challenge. The theory behind the development of oncolytic viruses is disarmingly simple. An arsenal of viruses would be developed, with genetically engineered, or natural, tropism for tumor cells. By seeding even just a few particles in a tumor, viral replication would amplify the therapeutic dose to high levels. Progeny virus would then rip through cancer cells in waves of lytic replication before reaching normal cells, at which point the infection would die away.2,3 The result would be a novel class of drug with a high therapeutic index. In theory, OV should outperform smallmolecule pharmaceuticals because of its intrinsic ability to amplify the therapeutic signal once delivered to the tumor. In addition, OV would, appealingly, use our wealth of knowledge on the molecular defects in cancer cells as the basis for the design of the tumor specificity of infection and replication.6 After initial concerns of creating a nightmarish new viral plague (cf. the 2007 movie I Am Legend), the market reaction to OV was favorable. However, with time, hurdles have emerged, and, as with the economy, the debates have begun. For example, is it possible for OV to be effective in the presence of a person’s immune system, in that a strong innate response to the virus will inevitably lead to extinction of viral replication, spread, and cancer cell lysis?7,8 Alternatively, and paradoxically, others have suggested that much of the efficacy of OV is directly attributable to the actions of an intact immune system,7,9 given that antivirus innate immune reactivity can lead to concomitant Molecular Therapy vol. 19 no. 11 november 2011
commentary clearance of tumor cells.10 Similarly, neutralizing antibodies (NAbs) to oncolytic viruses will already be present either in prevaccinated or infected subjects or will inevitably be formed de novo by virus administration. Is this good (protecting the patient from widespread dissemination and toxicity) or bad (inhibiting access of the circulating virus to disseminated tumor sites)?11 The apparently mutually exclusive nature of these opposing viewpoints is alarmingly similar to that of the contradictory standoff between fiscal economists. In both cases, the successful way forward will almost certainly come from a middle-ground approach, incorporating elements of both extremes. Compromise of opposing viewpoints is often more readily achieved when there is overall optimism about the bigger picture. In the case of OV, such optimism has been lacking because of the absence of an answer to the Great Unanswered Question: will it be possible to deliver an oncolytic virus, in a truly systemic fashion, in the face of the full force of a patient’s immune system and other antiviral barriers, to metastatic sites where it can replicate specifically in tumor? Although an unequivocal answer to this question has not yet emerged, there have been stimulus packages to shore up confidence. Thus, various types of cells have been used successfully to carry viruses to tumors, even in the presence of NAb- and complement-mediated antiviral clearance mechanisms.12,13 In addition, combination approaches have enhanced both delivery and efficacy.14–17 Nevertheless, in the absence of successful clinical data addressing the Great Unanswered Question, the long-term value of OV as the next big anticancer drug has remained in doubt. In their high-profile article, Breitbach et al. report on a phase I dose-escalation clinical study in which JX-594, an oncolytic poxvirus, was delivered intravenously to 23 patients with advanced treatment-refractory solid tumors.1 This is by no means the first report of the use of OV in humans, or even of a trial using systemic delivery,18 so why, you might ask, is this such a big deal? The answer is that the study provides unequivocal evidence that intravenous delivery of this virus can result in delivery to the tumor. Ten days after a single
intravenous infusion, virus was detected in tumor biopsy specimens by both polymerase chain reaction and immunohistochemistry. Interestingly, these results were obtained only at the highest dose level. Viral gene expression (actually from the b-gal transgene) was detected within tumor tissue, surrounded by very low levels of expression in normal tissue. These findings have added value in several ways. All the subjects had previously been vaccinated against smallpox, although only six had detectable antibody. Importantly, virus delivery to tumor was shown in at least one of these individuals, showing that vaccinia virus can be delivered systemically despite the presence of NAbs. Moreover, a dose-related antitumor activity was suggested, which correlated well with evidence of viral delivery to tumors. Although reports of clinical efficacy in similar trials are not uncommon,18 it is difficult not to be heartened by the overall package, which suggests that a critical threshold of intravenous virus infusion leads to intratumoral virus infection, subsequent viral replication, and possible clinical benefit. Of course, no clinical study, especially a phase I trial such as this, can keep all of the people happy all of the time, and a nagging question remains. The authors have demonstrated systemic virus delivery to tumors but fall tantalizingly short of proving that the virus, once there, actually replicates, although there is a plethora of supportive data. Intratumoral staining is highly suggestive of “virus factories.” Intratumoral expression of b-gal from the virus is (probably) dependent on replication, and detection of antibody to b-gal in patients confirms expression of this viral transgene. It is also difficult to believe that the distribution of gene expression seen in the tumors could be achieved without viral amplification, although peaks in serum levels of granulocyte–macrophage colony-stimulating factor (the product of a second transgene expressed by JX-594) following virus infusion again suggest that viral genes were expressed in vivo. However, the findings did not include recovery of live virus from tumor biopsy specimens, meaning (at the risk of being hypercritical) that formal proof is lacking that delivery, infection, and expression in fact equate with viral replication. 1931
© The American Society of Gene & Cell Therapy
commentary Encouraging as these results are, it remains to be seen whether all oncolytic viruses will be as amenable to systemic delivery. JX-594 may be one of the best cases, in that vaccinia has evolved specific viral forms that facilitate spread through the body, thereby evading both NAb- and complement-mediated inact ivation.19,20 However, the ability of many viruses to spread through infected hosts suggests that vaccinia is unlikely to be the only successful systemic traveler following intravenous delivery.18 An exciting avenue for further studies will be to characterize, and then exploit, the precise mechanisms that viruses use to persist in the circulation long enough to reach tumors. Interestingly, the authors detected virus in the whole blood of patients, but whether those viral particles were going it alone or hitching a ride on circulating cells21 was not clear. Several groups have shown that OV can both “ride and hide” on blood-derived cells, and identifying cells that show an increased propensity to traffic into tumors may provide opportunities for enhancing virus delivery in the future.12,13,21 In addition to the current findings with vaccinia, the OV portfolio recently received another important market boost from the herpes simplex virus department.22 That success, combined
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with the current report1 and progress of other oncolytic viruses to phase III clinical trials,18 should instill considerable confidence in the marketplace that OV represents a sound investment. Does the article by Breitbach and colleagues1 provide justification for a huge end-of-year bonus for OV enthusiasts? Probably not, at least not unless further positive reports emerge from randomized trials—and even then, the final market analysis is likely to remain significantly in the hands of those notoriously contrary economists. References
1. Breitbach, CJ, Burke, J, Jonker, D, Stephenson, J, Haas, AR and Chow, LQM (2011). Intravenous delivery of a multi-mechanistic cancer-targeted oncolytic poxvirus in humans. Nature 477: 99–102. 2. Chiocca, EA (2002). Oncolytic viruses. Nat Rev Cancer 2: 938–950. 3. Kirn, D, Martuza, RL and Zwiebel, J (2001). Replication-selective virotherapy for cancer: biological principles, risk management and future directions. Nat Med 7: 781–787. 4. Policy failure on a massive scale. The Economist 28 July 2011. 5. Cut or loose: history suggests that austerity and growth just do not mix. The Economist 14 July 2011. 6. Hanahan, D and Weinberg, RA (2011). Hallmarks of cancer: the next generation. Cell 144: 646–674. 7. Chiocca, EA (2008). The host response to cancer virotherapy. Curr Opin Mol Ther 10: 38–45. 8. Fulci, G, Breymann, L, Gianni, D, Kurozomi, K, Rhee, SS, Yu, J et al. (2006). Cyclophosphamide enhances glioma virotherapy by inhibiting innate immune responses. Proc Natl Acad Sci USA 103: 12873–12878. 9. Prestwich, RJ, Errington, F, Diaz, RM, Pandha, HS, Harrington, KJ, Melcher, AA et al. (2009). The case of oncolytic viruses versus the immune system: waiting on the judgment of Solomon. Hum Gene Ther 20: 1119–1132.
10. Wongthida, P, Diaz, RM, Galivo, F, Kottke, T, Thompson, J, Melcher, A et al. (2011). VSV oncolytic virotherapy in the B16 model depends upon intact MyD88 signaling. Mol Ther 19: 150–158. 11. Fisher, K (2006). Striking out at disseminated metastases: the systemic delivery of oncolytic viruses. Curr Opin Mol Ther 8: 301–313. 12. Nakashima, H, Kaur, B and Chiocca, EA (2010). Directing systemic oncolytic viral delivery to tumors via carrier cells. Cyto Growth Factor Rev 21: 119–126. 13. Power, AT and Bell, JC (2008). Taming the Trojan horse: optimizing dynamic carrier cell/oncolytic virus systems for cancer biotherapy. Gene Ther 15: 772–779. 14. Harrington, KJ, Melcher, A, Vassaux, G, Pandha, HS and Vile, RG (2008). Exploiting synergies between radiation and oncolytic viruses. Curr Opin Mol Ther 10: 362–370. 15. Kottke, T, Chester, J, Ilett, E, Thompson, J, Diaz, R, Coffey, M (2011). Precise scheduling of chemotherapy primes VEGF-producing tumors for successful systemic oncolytic virotherapy. Mol Ther 19: 1802–1812. 16. Ottolino-Perry, K, Diallo, JS, Lichty, BD, Bell, JC and McCart, JA (2010). Intelligent design: combination therapy with oncolytic viruses. Mol Ther 18: 251–263. 17. Wennier, ST, Liu, J and McFadden, G (2011). Bugs and drugs: oncolytic virotherapy in combination with chemotherapy. Curr Pharm Biotechnol; e-pub ahead of print 8 July 2011. 18. Donnelly, OG, Errington-Mais, F, Prestwich, R, Harrington, K, Pandha, H, Vile, R et al. (2011). Recent clinical experience with oncolytic viruses. Curr Pharm Biotechnol; e-pub ahead of print 8 July 2011. 19. Vanderplasschen, A, Hollinshead, M and Smith, GL (1997). Antibodies against vaccinia virus do not neutralize extracellular enveloped virus but prevent virus release from infected cells and comet formation. J Gen Virol 78: 2041–2048. 20. Vanderplasschen, A, Mathew, E, Hollinshead, M, Sim, RB and Smith, GL (1998). Extracellular enveloped vaccinia virus is resistant to complement because of incorporation of host complement control proteins into its envelope. Proc Natl Acad Sci USA 95: 7544–7549. 21. Willmon, C, Harrington, K, Kottke, T, Prestwich, R, Melcher, A and Vile, R (2009). Cell carriers for oncolytic viruses: Fed Ex for cancer therapy. Mol Ther 17: 1667–1676. 22. Evans, J (2011). Recent deal highlights hopes for cancer-killing viruses. Nat Med 17: 268–269.
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Kochenderfer, JN, Wilson, WH, Janik, JE, Dudley, ME, Stetler-Stevenson, M, Feldman, SA et al. (2010). Eradication of B-lineage cells and regression of lymphoma in a patient treated with autologous T cells genetically engineered to recognize CD19. Blood 116: 4099–4102. Porter, DL, Levine, BL, Kalos, M, Bagg, A and June, CH (2011). Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia. N Engl J Med 365: 725–733. Kalos, M, Levine, BL, Porter, DL, Katz, S, Grupp, SA, Bagg, A et al. (2011). T cells with chimeric antigen receptors have potent antitumor effects and can establish memory in patients with advanced leukemia. Sci Transl Med 3: 95ra73. Brentjens, RJ, Rivière, I, Park, JH, Davila, ML, Wang, X, Stefanski, J et al. (2011). Safety and persistence of adoptively transferred autologous CD19-targeted T cells in patients with relapsed or chemotherapy refractory B-cell leukemias. Blood; e-pub ahead of print 17 August 2011. Dudley, ME, Wunderlich, JR, Robbins, PF, Yang, JC, Hwu, P, Schwartzentruber, DJ et al. (2002). Cancer regression and autoimmunity in patients after clonal repopulation with anti-tumor lymphocytes. Science 298: 850–854. Dudley, ME, Yang, JC, Sherry, R, Hughes, MS, Royal, R, Kammula, U et al. (2008). Adoptive cell therapy for patients with metastatic melanoma: evaluation of intensive myeloablative chemoradiation preparative regimens. J Clin Oncol 26: 5233–5239. Rosenberg, SA, Yang, JC, Sherry, RM, Kammula, US, Hughes, MS, Phan, GQ et al. (2011). Durable complete responses in heavily pretreated patients with metastatic melanoma using T-cell transfer immunotherapy. Clin Cancer Res 17: 4550–4557. Rosenberg, SA, Restifo, NP, Yang, JC, Morgan, RA and Dudley, ME (2008). Adoptive cell transfer: a clinical path to effective cancer immunotherapy. Nat Rev Cancer 8: 299–308. Rosenberg, SA (2011). Cell transfer immunotherapy for metastatic solid cancer—what clinicians need to know. Nat Rev Clin Oncol; e-pub ahead of print 2 August 2011. Morgan, RA, Dudley, ME, Wunderlich, JR, Hughes, MS, Yang, JC, Sherry, RM et al. (2006). Cancer regression in patients after transfer of genetically engineered lymphocytes. Science 314: 126–129. Johnson, LA, Morgan, RA, Dudley, ME, Cassard, L, Yang, JC, Hughes, MS et al. (2009). Gene therapy with human and mouse T-cell receptors mediates cancer regression and targets normal tissues expressing cognate antigen. Blood 114: 535–546. Morgan, RA, Dudley, ME and Rosenberg, SA (2010). Adoptive cell therapy: genetic modification to redirect effector cell specificity. Cancer J 16: 336–341. Gross, G, Waks, T and Eshhar Z (1989). Expression of immunoglobulin-T-cell receptor chimeric molecules as functional receptors with antibody-type specificity. Proc Natl Acad Sci USA 86: 10024–10028. Hwu, P, Yang, JC, Cowherd, R, Treisman, J, Shafer, GE and Rosenberg, SA (1995). In vivo antitumor activity of T-cells redirected with chimeric antibody/T-cell receptor genes. Cancer Res 55: 3369–3373. Kershaw, MH, Westwood, JA, Parker, LL, Wang, G, Eshhar, Z, Mavroukakis, SA et al. (2006). A phase I study on adoptive immunotherapy using gene-modified T cells for ovarian cancer. Clin Cancer Res 12: 6106–6115. Lamers, CHJ, Sleiffer, S, Vulto, AG, Kruit, WH, Kliffen, M, Debets, R et al. (2006). Treatment of metastatic renal cell carcinoma with autologous T-lymphocytes genetically retargeted against carbonic anhydrase IX: first clinical experience. J Clin Oncol 24: e20–e22. Pule, MA, Savoldo, B, Myers, GD, Rossig, C, Russell, HV, Dotti, G et al. (2008). Virus-specific T cells engineered to coexpress tumor-specific receptors: persistence and antitumor activity in individuals with neuroblastoma. Nat Med 14: 1264–1270. Simpson, AJ, Caballero, OL, Jungbluth, A, Chen, YT and Old, LJ (2005). Cancer/testis antigens, gametogenesis and cancer. Nat Rev Cancer 5: 615–625. Robbins, PF, Morgan, RA, Feldman, SA, Yang, JC, Sherry, RM, Dudley, ME et al. (2011). Tumor regression in patients with metastatic synovial sarcoma and melanoma using genetically engineered lymphocytes reactive with NY-ESO-1. J Clin Oncol 29: 917–924. Chinnasamy, N, Wargo, JA, Yu, Z, Rao, M, Frankel, TL, Riley, JP et al. (2011). A TCR targeting the HLA-A*01restricted epitope of MAGE-A3 recognizes multiple epitopes of the MAGE-A antigen superfamily in several types of cancer. J Immunol 186: 685–696.
1930
21. Parkhurst, MR, Yang, JC, Langan, RC, Dudley, ME, Nathan, DA, Feldman, SA et al. (2011). T cells targeting carcinoembryonic antigen can mediate regression of metastatic colorectal cancer but induce severe transient colitis. Mol Ther 19: 620–626. 22. Morgan, RA, Yang, JC, Kitano, M, Dudley, ME, Laurencot, CM and Rosenberg, SA (2010). Case report of a serious adverse event following the administration of T cells transduced with a chimeric antigen receptor recognizing ERBB2. Mol Ther 18: 843–851. 23. Brentjens, RJ, Latouche, JB, Santos, E, Marti, F, Gong, MC, Lyddane, C et al. (2003). Eradication of systemic B-cell tumors by genetically targeted human T lymphocytes co-stimulated by CD80 and interleukin-15. Nat Med 9: 279–286. 24. Cooper, LJ, Topp, MS, Serrano, LM, Gonzalez, S, Chang, WC, Naranjo, A et al. (2003). T-cell clones can be rendered specific for CD19: toward the selective augmentation of the graft-versus-B lineage leukemia effect. Blood 101: 1637–1644. 25. Brentjens, RJ, Santos, E, Nikhamin, Y, Yeh, R, Matsushita, M, La Perle, K et al. (2007). Genetically targeted T cells eradicate systemic acute lymphoblastic leukemia xenografts. Clin Cancer Res 13: 5426–5435. 26. Cheadle, EJ, Hawkins, RE, Batha, H, O’Neill, AL, Dovedi, SJ and Gilham, DE (2010). Natural expression of the CD19 antigen impacts the long-term engraftment but not antitumor activity of CD19-specific engineered T cells. J Immunother 184: 1885–1896. 27. Imai, C, Mihara, K, Andreansky, M, Nicholson, IC, Pui, CH, Geiger, TL et al. (2004). Chimeric receptors with 4-1BB signaling capacity provoke potent cytotoxicity against acute lymphoblastic leukemia. Leukemia 18: 678–684. 28. Kowolik, CM, Topps, MS, Gonzalez, S, Pfeiffer, T, Olivares, S, Gonzalez, N et al. (2006). CD28 costimulation provided through a CD19-specific chimeric antigen receptor enhances in vivo persistence and antitumor efficacy of adoptively transferred T cells. Cancer Res 66: 10995–11004. 29. Milone, MC, Fish, JD, Carpenito, C, Carroll, RG, Binder, GK, Teachey, D et al. (2009). Chimeric receptors containing CD137 signal transduction domains mediate enhanced survival of T cells and increased antileukemic efficacy in vivo. Mol Ther 17: 1453–1464. 30. Rossig, C, Bär, A, Pscherer, S, Altvater, B, Pule, M, Rooney, CM et al. (2006). Target antigen expression on a professional antigen-presenting cell induces superior proliferative antitumor T-cell responses via chimeric T-cell receptors. J Immunother 29: 21–31. 31. Jensen, MC, Popplewell, L, Cooper, LJ, DiGiusto, D, Kalos, M, Ostberg, JR et al. (2010). Antitransgene
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rejection responses contribute to attenuated persistence of adoptively transferred CD20/CD19-specific chimeric antigen receptor redirected T cells in humans. Biol Blood Marrow Transplant 16: 1245–1256. Kochenderfer, JN, Feldman, SA, Zhao, Y, Xu, H, Black, MA, Morgan, RA et al. (2009). Construction and preclinical evaluation of an anti-CD19 chimeric antigen receptor. J Immunother 32: 689–702. Kochenderfer, JN, Yu, Z, Frasheri, D, Restifo, NP and Rosenberg, SA (2010). Adoptive transfer of syngeneic T cells transduced with a chimeric antigen receptor that recognizes murine CD19 can eradicate lymphoma and normal B cells. Blood 116: 3875–3886. Brentjens, R, Yeh, R, Bernal, Y, Riviere, I and Sadelain, M (2010). Treatment of chronic lymphocytic leukemia with genetically targeted autologous T cells: case report of an unforeseen adverse event in a phase 1 clinical trial. Mol Ther 18: 666–668. Savoldo, B, Ramos, CA, Liu, E, Mims, MP, Keating, MJ, Carrum, G et al. (2011). CD28 costimulation improves expansion and persistence of chimeric antigen receptormodified T cells in lymphoma patients. J Clin Invest 121: 1822–1826. Klebanoff, CA, Gattinoni, L, Palmer, DC, Muranski, P, Ji, Y, Hinrichs, CS et al. (2011). Determinants of successful CD8+ T-cell adoptive immunotherapy for large established tumors in mice. Clin Cancer Res 17: 5343–5352. Gattinoni, L, Powell, DJ, Rosenberg, SA and Restifo, NP (2006). Adoptive immunotherapy for cancer: building on success. Nat Rev Immunol 6: 383–393. Bonini, C, Brenner, MK, Heslop, HE and Morgan, RA (2011). Genetic modification of T cells. Biol Blood Marrow Transplant 17: S15–S20. Tey, S, Dotti, G, Rooney, CM, Heslop, HE and Brenner, MK (2007). Inducible caspase 9 suicide gene to improve the safety of allodepleted T cells after haploidentical stem cell transplantation. Biol Blood Marrow Transplant 13: 913–924. Liu, K and Rosenberg, SA (2001). Transduction of an interleukin-2 gene into human melanoma-reactive lymphocytes results in their continued growth in the absence of exogenous IL-2 and maintenance of specific antitumor activity. J Immunol 167: 6356–6365. Kerkar, SP, Muranski, P, Kaiser, A, Boni, A, SanchezPerez, L, Yu, Z et al. (2010). Tumor-specific CD8+ T cells expressing interleukin-12 eradicate established cancers in lymphodepleted hosts. Cancer Res 70: 6725–6734. Stephan, MT, Ponomarev, V, Brentjens, RJ, Chang, AH, Dobrenkov, KV, Heller, G et al. (2007). T cell–encoded CD80 and 4-1BBL induce auto- and transcostimulation, resulting in potent tumor rejection. Nat Med 13: 1440–1449.
An Intravenous Stimulus Package for Oncolytic Virotherapy Richard Vile1,2 and Alan Melcher2 doi:10.1038/mt.2011.217
A
recently published phase I clinical trial shows that an oncolytic
1 Departments of Molecular Medicine and Immunology, Mayo Clinic, Rochester, Minnesota, USA; 2Leeds Institute of Molecular Medicine and Cancer Research UK Clinical Centre, St. James’ University Hospital, Leeds, UK Correspondence: Richard Vile, Mayo Clinic, Guggenheim 18, 200 First Street SW, Rochester, Minnesota 55905, USA. E-mail: [email protected]
vaccinia virus, JX-594, can reach and infect tumors following a single intravenous infusion, despite the barriers to systemic virus spread.1 Direct evidence of virus localization in tumors, along with a portfolio of supportive data, suggests that virus can also replicate selectively in tumors. These data come extremely close to validating the basic principles underlying the development of replicating viruses for cancer therapy.2,3
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The impending collapse of the world’s financial apparatus4 is generally unnerving, but the most concerning aspect is the radically divergent solutions proposed by the politicians and economists whose job it is to pull us back from the precipice—should we spend our way out of recession or make deep cuts to balance the budget?5 Although the success, or otherwise, of oncolytic virotherapy (OV) may have rather less global significance to most people than the financial meltdown, to analysts monitoring the “futures” of novel cancer therapies, the debates surrounding OV appear to have become as contradictory, and bewilderingly polarized, as those addressing the current politico-economic challenge. The theory behind the development of oncolytic viruses is disarmingly simple. An arsenal of viruses would be developed, with genetically engineered, or natural, tropism for tumor cells. By seeding even just a few particles in a tumor, viral replication would amplify the therapeutic dose to high levels. Progeny virus would then rip through cancer cells in waves of lytic replication before reaching normal cells, at which point the infection would die away.2,3 The result would be a novel class of drug with a high therapeutic index. In theory, OV should outperform smallmolecule pharmaceuticals because of its intrinsic ability to amplify the therapeutic signal once delivered to the tumor. In addition, OV would, appealingly, use our wealth of knowledge on the molecular defects in cancer cells as the basis for the design of the tumor specificity of infection and replication.6 After initial concerns of creating a nightmarish new viral plague (cf. the 2007 movie I Am Legend), the market reaction to OV was favorable. However, with time, hurdles have emerged, and, as with the economy, the debates have begun. For example, is it possible for OV to be effective in the presence of a person’s immune system, in that a strong innate response to the virus will inevitably lead to extinction of viral replication, spread, and cancer cell lysis?7,8 Alternatively, and paradoxically, others have suggested that much of the efficacy of OV is directly attributable to the actions of an intact immune system,7,9 given that antivirus innate immune reactivity can lead to concomitant Molecular Therapy vol. 19 no. 11 november 2011
commentary clearance of tumor cells.10 Similarly, neutralizing antibodies (NAbs) to oncolytic viruses will already be present either in prevaccinated or infected subjects or will inevitably be formed de novo by virus administration. Is this good (protecting the patient from widespread dissemination and toxicity) or bad (inhibiting access of the circulating virus to disseminated tumor sites)?11 The apparently mutually exclusive nature of these opposing viewpoints is alarmingly similar to that of the contradictory standoff between fiscal economists. In both cases, the successful way forward will almost certainly come from a middle-ground approach, incorporating elements of both extremes. Compromise of opposing viewpoints is often more readily achieved when there is overall optimism about the bigger picture. In the case of OV, such optimism has been lacking because of the absence of an answer to the Great Unanswered Question: will it be possible to deliver an oncolytic virus, in a truly systemic fashion, in the face of the full force of a patient’s immune system and other antiviral barriers, to metastatic sites where it can replicate specifically in tumor? Although an unequivocal answer to this question has not yet emerged, there have been stimulus packages to shore up confidence. Thus, various types of cells have been used successfully to carry viruses to tumors, even in the presence of NAb- and complement-mediated antiviral clearance mechanisms.12,13 In addition, combination approaches have enhanced both delivery and efficacy.14–17 Nevertheless, in the absence of successful clinical data addressing the Great Unanswered Question, the long-term value of OV as the next big anticancer drug has remained in doubt. In their high-profile article, Breitbach et al. report on a phase I dose-escalation clinical study in which JX-594, an oncolytic poxvirus, was delivered intravenously to 23 patients with advanced treatment-refractory solid tumors.1 This is by no means the first report of the use of OV in humans, or even of a trial using systemic delivery,18 so why, you might ask, is this such a big deal? The answer is that the study provides unequivocal evidence that intravenous delivery of this virus can result in delivery to the tumor. Ten days after a single
intravenous infusion, virus was detected in tumor biopsy specimens by both polymerase chain reaction and immunohistochemistry. Interestingly, these results were obtained only at the highest dose level. Viral gene expression (actually from the b-gal transgene) was detected within tumor tissue, surrounded by very low levels of expression in normal tissue. These findings have added value in several ways. All the subjects had previously been vaccinated against smallpox, although only six had detectable antibody. Importantly, virus delivery to tumor was shown in at least one of these individuals, showing that vaccinia virus can be delivered systemically despite the presence of NAbs. Moreover, a dose-related antitumor activity was suggested, which correlated well with evidence of viral delivery to tumors. Although reports of clinical efficacy in similar trials are not uncommon,18 it is difficult not to be heartened by the overall package, which suggests that a critical threshold of intravenous virus infusion leads to intratumoral virus infection, subsequent viral replication, and possible clinical benefit. Of course, no clinical study, especially a phase I trial such as this, can keep all of the people happy all of the time, and a nagging question remains. The authors have demonstrated systemic virus delivery to tumors but fall tantalizingly short of proving that the virus, once there, actually replicates, although there is a plethora of supportive data. Intratumoral staining is highly suggestive of “virus factories.” Intratumoral expression of b-gal from the virus is (probably) dependent on replication, and detection of antibody to b-gal in patients confirms expression of this viral transgene. It is also difficult to believe that the distribution of gene expression seen in the tumors could be achieved without viral amplification, although peaks in serum levels of granulocyte–macrophage colony-stimulating factor (the product of a second transgene expressed by JX-594) following virus infusion again suggest that viral genes were expressed in vivo. However, the findings did not include recovery of live virus from tumor biopsy specimens, meaning (at the risk of being hypercritical) that formal proof is lacking that delivery, infection, and expression in fact equate with viral replication. 1931
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commentary Encouraging as these results are, it remains to be seen whether all oncolytic viruses will be as amenable to systemic delivery. JX-594 may be one of the best cases, in that vaccinia has evolved specific viral forms that facilitate spread through the body, thereby evading both NAb- and complement-mediated inact ivation.19,20 However, the ability of many viruses to spread through infected hosts suggests that vaccinia is unlikely to be the only successful systemic traveler following intravenous delivery.18 An exciting avenue for further studies will be to characterize, and then exploit, the precise mechanisms that viruses use to persist in the circulation long enough to reach tumors. Interestingly, the authors detected virus in the whole blood of patients, but whether those viral particles were going it alone or hitching a ride on circulating cells21 was not clear. Several groups have shown that OV can both “ride and hide” on blood-derived cells, and identifying cells that show an increased propensity to traffic into tumors may provide opportunities for enhancing virus delivery in the future.12,13,21 In addition to the current findings with vaccinia, the OV portfolio recently received another important market boost from the herpes simplex virus department.22 That success, combined
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with the current report1 and progress of other oncolytic viruses to phase III clinical trials,18 should instill considerable confidence in the marketplace that OV represents a sound investment. Does the article by Breitbach and colleagues1 provide justification for a huge end-of-year bonus for OV enthusiasts? Probably not, at least not unless further positive reports emerge from randomized trials—and even then, the final market analysis is likely to remain significantly in the hands of those notoriously contrary economists. References
1. Breitbach, CJ, Burke, J, Jonker, D, Stephenson, J, Haas, AR and Chow, LQM (2011). Intravenous delivery of a multi-mechanistic cancer-targeted oncolytic poxvirus in humans. Nature 477: 99–102. 2. Chiocca, EA (2002). Oncolytic viruses. Nat Rev Cancer 2: 938–950. 3. Kirn, D, Martuza, RL and Zwiebel, J (2001). Replication-selective virotherapy for cancer: biological principles, risk management and future directions. Nat Med 7: 781–787. 4. Policy failure on a massive scale. The Economist 28 July 2011. 5. Cut or loose: history suggests that austerity and growth just do not mix. The Economist 14 July 2011. 6. Hanahan, D and Weinberg, RA (2011). Hallmarks of cancer: the next generation. Cell 144: 646–674. 7. Chiocca, EA (2008). The host response to cancer virotherapy. Curr Opin Mol Ther 10: 38–45. 8. Fulci, G, Breymann, L, Gianni, D, Kurozomi, K, Rhee, SS, Yu, J et al. (2006). Cyclophosphamide enhances glioma virotherapy by inhibiting innate immune responses. Proc Natl Acad Sci USA 103: 12873–12878. 9. Prestwich, RJ, Errington, F, Diaz, RM, Pandha, HS, Harrington, KJ, Melcher, AA et al. (2009). The case of oncolytic viruses versus the immune system: waiting on the judgment of Solomon. Hum Gene Ther 20: 1119–1132.
10. Wongthida, P, Diaz, RM, Galivo, F, Kottke, T, Thompson, J, Melcher, A et al. (2011). VSV oncolytic virotherapy in the B16 model depends upon intact MyD88 signaling. Mol Ther 19: 150–158. 11. Fisher, K (2006). Striking out at disseminated metastases: the systemic delivery of oncolytic viruses. Curr Opin Mol Ther 8: 301–313. 12. Nakashima, H, Kaur, B and Chiocca, EA (2010). Directing systemic oncolytic viral delivery to tumors via carrier cells. Cyto Growth Factor Rev 21: 119–126. 13. Power, AT and Bell, JC (2008). Taming the Trojan horse: optimizing dynamic carrier cell/oncolytic virus systems for cancer biotherapy. Gene Ther 15: 772–779. 14. Harrington, KJ, Melcher, A, Vassaux, G, Pandha, HS and Vile, RG (2008). Exploiting synergies between radiation and oncolytic viruses. Curr Opin Mol Ther 10: 362–370. 15. Kottke, T, Chester, J, Ilett, E, Thompson, J, Diaz, R, Coffey, M (2011). Precise scheduling of chemotherapy primes VEGF-producing tumors for successful systemic oncolytic virotherapy. Mol Ther 19: 1802–1812. 16. Ottolino-Perry, K, Diallo, JS, Lichty, BD, Bell, JC and McCart, JA (2010). Intelligent design: combination therapy with oncolytic viruses. Mol Ther 18: 251–263. 17. Wennier, ST, Liu, J and McFadden, G (2011). Bugs and drugs: oncolytic virotherapy in combination with chemotherapy. Curr Pharm Biotechnol; e-pub ahead of print 8 July 2011. 18. Donnelly, OG, Errington-Mais, F, Prestwich, R, Harrington, K, Pandha, H, Vile, R et al. (2011). Recent clinical experience with oncolytic viruses. Curr Pharm Biotechnol; e-pub ahead of print 8 July 2011. 19. Vanderplasschen, A, Hollinshead, M and Smith, GL (1997). Antibodies against vaccinia virus do not neutralize extracellular enveloped virus but prevent virus release from infected cells and comet formation. J Gen Virol 78: 2041–2048. 20. Vanderplasschen, A, Mathew, E, Hollinshead, M, Sim, RB and Smith, GL (1998). Extracellular enveloped vaccinia virus is resistant to complement because of incorporation of host complement control proteins into its envelope. Proc Natl Acad Sci USA 95: 7544–7549. 21. Willmon, C, Harrington, K, Kottke, T, Prestwich, R, Melcher, A and Vile, R (2009). Cell carriers for oncolytic viruses: Fed Ex for cancer therapy. Mol Ther 17: 1667–1676. 22. Evans, J (2011). Recent deal highlights hopes for cancer-killing viruses. Nat Med 17: 268–269.
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