CANCER IMMUNOTHERAPY OVERVIEW OF CURRENT LANDSCAPE

2018 AMWA Annual Meeting 1 November 2018 Petra Volna, Senior Regulatory Documentation Scientist Genentech Inc. When Was Cancer Immunotherapy First Used?

Hint: The answer may surprise you

FOR EDUCATIONAL PURPOSES ONLY 2 2 William B. Coley, MD: The Father of Immunotherapy

FOR EDUCATIONAL PURPOSES ONLY 3 3 The Nobel Prize in Physiology or Medicine 1908 Awarded jointly to Ilya Mechnikov and Paul Ehrlich "in recognition of their work on immunity."

FOR EDUCATIONAL PURPOSES ONLY 4 The Nobel Prize in Physiology or Medicine 2011 One half awarded jointly to jointly to Bruce A. Beutler and Jules A. Hoffmann "for their discoveries concerning the activation of innate immunity" and the other half to Ralph M. Steinman "for his discovery of the dendritic cell and its role in adaptive immunity."

Ralph M. Steinman

FOR EDUCATIONAL PURPOSES ONLY 5 Dendritic cells (DCs) have the unique capacity to initiate primary and secondary immune responses

Maturation in situ

Early

Intermediate

Late

Pierre P. et al. Nature. 1997;388:787-92 FOR EDUCATIONAL PURPOSES ONLY Discovery of T-cell Growth Factor (Interleukin-2)

ElectronGillian MicroscopyM Griffiths, Facility Cambridge at The ImmunologyNational Cancer Network Institute atUniversity Frederick (NCIof Cambridge-Frederick) FOR EDUCATIONAL PURPOSES ONLY 7 T-cell-mediated Cytotoxicity against Autologous Malignant Melanoma

Out of 13 patients recurrent or metastatic malignant melanoma, only 1 patient, a 31-year-old male, who underwent resections of extensive metastatic melanoma of axillary, supraclavicular, and cervical lymph nodes in 1976 and 1978 and remained free of detectable melanoma. This patient’s lymphocytes were found to be strongly cytotoxic for autologous cultured melanoma cells

FOR EDUCATIONAL PURPOSES ONLY 8 Binding of immunogenic peptides to Ia histocompatibility molecules

FOR EDUCATIONAL PURPOSES ONLY 9 Immunological Synapse Created

Gillian M Griffiths, Cambridge Immunology Network University of Cambridge

FOR EDUCATIONAL PURPOSES ONLY 10 Key steps for effective immune response

• Effective antigen presentation • T-cell infiltration • Tumor or pathogen killing • Immunologic memory • High-affinity antibodies and memory T and B cells

FOR EDUCATIONAL PURPOSES ONLY 11 11 CANCER-IMMUNE EQUILIBRIUM Elimination, Equilibrium and Escape

Immunoediting: Nonsilent point mutations (which lead to antigenic neoepitopes) are more frequently lost in cancers compared with silent point mutations (not recognized by T cells)

Adaptive Immune Resistance: Tumor antigen-specific T cells attempt to attack the cancer, but the cancer changes in a reactive fashion to protect itself from this immune attack

Ribas A. Cancer Discov. 2015 5(9):915-9 FOR EDUCATIONAL PURPOSES ONLY 13 Cancer Immunity Cycle and Immune Phenotypes Priming and activation (APCs and T cells) T-cell trafficking

T-cell infiltration (T cells and endothelial cells) Antigen presentation (dendritic cells/APCs)

T-cell recognition Antigen release

T-cell–mediated killing of tumor cells Chen DS, Mellman I. Immunity. 2013;39:1-10 Chen DS, Mellman I. Nature. 2017;541:321-330

FOR EDUCATIONAL PURPOSES ONLY 14 Types of Cancer Immunotherapy (CIT)

Key to all forms of CIT: • Immune checkpoint blockade Effective antigen presentation • Dendritic cells and Therapeutic cancer vaccines •T-cell infiltration • Chimeric antigen receptor •Tumor killing via CTLs (CAR) T cells • T-cell recruiting bispecific antibodies • Preventative vaccines

FOR EDUCATIONAL PURPOSES ONLY 15 IMMUNE CHECKPOINT BLOCKADE

Allison Bruce The Nobel Prize in Physiology or Medicine 2018 Awarded jointly to James P. Allison and Tasuku Honjo "for their discovery of cancer therapy by inhibition of negative immune regulation." One of several scientists Discovery of PD-1 and who had made the its importance for observation that CTLA-4 cancer therapy functions as a brake on PD-1 is a protein T cells expressed on the Investigated CTLA-4 surface of T cells that blockade to disengage functions as a T-cell the T-cell brake and brake unleash the immune system to attack cancer cells

James P. Allison Tasuku Honjo

FOR EDUCATIONAL PURPOSES ONLY Immune Checkpoint Inhibitors

2010 2014 Improved survival with ipilimumab, Opdivo, nivolumab, a PD-1-specific CTLA-4-specific antibody, in antibody approved in Japan for patients with metastatic melanoma advanced melanoma 1994 2001 CTLA-4 identified as negative B7-H1 (PD-L1) and B7-DC (PD-L2) 2010 2014 regulator of T-cell activation identified as ligands for PD-1 PD-1-specific antibody, induces FDA approves Keytruda, 1996 2003 frequent tumor regressions in pembrolizumab, for advanced CTLA-4 blockade could CTLA-4-specific antibody patients with advanced melanoma, melanoma cause tumor rejection induces clinical renal, lung and colon cancer 2015 in mice regressions in patients 2011 FDA approves Tecentriq, 1999 with advanced melanoma PD-1 Identified as FDA approves Yervoy, ipilimumab, atezolizumab, for bladder immune checkpoint for advanced melanoma cancer 2012 Anti-PD-1 antibody shows dramatic efficacy results in Ph 1 trial

1995 2000 2005 2010 2015

FOR EDUCATIONAL PURPOSES ONLY 18 How Do Immune Checkpoint Inhibitors Work? Activation of T cells requires PD-1 is another T-cell that the T-cell receptor binds brake that inhibits T-cell to structures on other activation immune cells recognized as ”non-self”. A protein functioning as a T-cell accelerator is also required for T cell activation. CTLA-4 functions as a brake on T cells that inhibits the function of the accelerator

Antibodies (green) against Antibodies against PD-1 inhibit CTLA-4 block the function of the function of the brake the brake leading to activation leading to activation of T cells of T cells and attack on cancer and highly efficient attack on cells. cancer cells. Graphic courtesy of The Nobel Foundation

FOR EDUCATIONAL PURPOSES ONLY Blockade of CTLA-4 and of PD-1 and PD-L1 to induce antitumor responses

Antoni Ribas, and Jedd D. Wolchok Science 2018;359:1350-1355 Published by AAAS FOR EDUCATIONAL PURPOSES ONLY 20 Timing of clinical development of anti–CTLA-4, anti–PD-1, and anti–PD-L1 antibodies from first administration to humans to FDA approval

Antoni Ribas, and Jedd D. Wolchok Science 2018;359:1350-1355 Published by AAAS FOR EDUCATIONAL PURPOSES ONLY 21 Too Much of a Good Thing? Trial explosion More than 1000 clinical trials are combining other cancer treatments with immunotherapy drugs, called checkpoint inhibitors, that target the proteins PD-1 or PD-L1 (bottom bars). The number of subjects needed for those trials has skyrocketed, and some trials may not find enough patients.*

Jocelyn Kaiser Science 2018;359:1346-1347

FOR EDUCATIONAL PURPOSES ONLY DENDRITIC CELLS AND THERAPEUTIC CANCER VACCINES

Magnification 16,000x. (Rita Serda/FEI Image) Dendritic cells and Therapeutic cancer vaccines

1998 2003 2005 2010 A landmark study showed First data indicating that Type, density, and location of immune cells FDA approves the use of that accumulation of CD8+ T presence of tumor-infiltrating within tumor samples found to be a better sipuleucel-T (Provenge®) for the cells within the tumor (TILs) lymphocytes in the primary predictor of patient survival than previous treatment of prostate cancer predicted improved patient tumor strongly correlated with pathological criteria for tumor staging survival patient survival 2011 Artificial antigen presenting cells 2003 2005 (aAPC) could successfully NKT cells enhance CD4+ and Rapid and strong human CD8+ T cell enhance adoptive therapy of tumor CD8+ T cell responses to soluble responses to vaccination with peptide, IFA, antigen-specific CD8+ T cells antigen in vivo through direct and CpG oligodeoxynucleotide interaction with dendritic cells 2011 2009 Peptide vaccine + IL-2 improves 2004 Mycobacterial cell wall-DNA melanoma responses 1992 The first tumor antigenic complex showed antineoplastic First characterization of peptides produced by activity in patients with bladder peptides from MHC class I peptide splicing reported cancer

2000 2005 2010

FOR EDUCATIONAL PURPOSES ONLY 24 Personalized Vaccines for Cancer Immunotherapy Customizing a patient-specific cancer vaccine

Ugur Sahin, and Özlem Türeci Science 2018;359:1355-1360 Published by AAAS FOR EDUCATIONAL PURPOSES ONLY 25

Neoepitope Vaccines Promote a Functional Cancer Immunity Cycle

Ugur Sahin, and Özlem Türeci Science 2018;359:1355-1360

FOR EDUCATIONAL PURPOSES ONLY 26

Personalized Cancer Medicine

Ugur Sahin, and Özlem Türeci Science 2018;359:1355-1360

FOR EDUCATIONAL PURPOSES ONLY 27

The Interconnected Dimensions of Cancer Heterogeneity

Ugur Sahin, and Özlem Türeci Science 2018;359:1355-1360

FOR EDUCATIONAL PURPOSES ONLY 28 Source: Sahin, U. et al. Nature 547, 222–226 (2017) CHIMERIC ANTIGEN RECEPTOR (CAR) T CELLS Meletios Verras / Getty Images

Magnification 16,000x. (Rita Serda/FEI Image) Chimeric antigen receptor (CAR) T cells

1992 2002 2007 2011 Primary T-cell engineering In vitro-expanded T cells can cause First IND for CD19 CAR Adoptive immunotherapy with CD8+ tumor regressions in advanced therapy (BB-IND#11411) T cells genetically engineering to 1993 melanoma recognize the NY-ESO-1 induce First generation of CARs 2006 remissions in sarcoma and 2002 (CD3ζ-based) Bulk T cells transduced with T cell melanoma 2017 Second generation of CARs receptor genes are used to treat FDA approves CD19 CAR (CD28-based) T therapy for pediatric ALL patients with melanoma 2011 and NHL 2003 New CAR T cell treatment Demonstration of CD19 cures patients with CLL as a valid target for CARs 2008 CAR T cells induce 2013 CAR T cell therapy 2004 clinical responses in patients with attains complete Third generation of CARs responses in ALL (4-1BB-based) B cell lymphomas

1995 2005 2010 2015

FOR EDUCATIONAL PURPOSES ONLY 32 CAR T cell immunotherapy for human cancer Engineered T cells: design of TCR versus CAR T cells

Carl H. June et al. Science 2018;359:1361-1365 Published by AAAS FOR EDUCATIONAL PURPOSES ONLY 33 CAR-T Cell Therapy Is Associated with Cytokine Release Syndrome and Neurotoxicity

Carl H. June et al. Science 2018;359:1361-1365 Published by AAAS FOR EDUCATIONAL PURPOSES ONLY 34 Conditionally Expressed CAR using Notch as a Signal Induction and Response Pathway System

Carl H. June et al. Science 2018;359:1361-1365 Published by AAAS FOR EDUCATIONAL PURPOSES ONLY 35 Regional disparities in studies of CAR T cell therapies

Carl H. June et al. Science 2018;359:1361-1365 Published by AAAS FOR EDUCATIONAL PURPOSES ONLY 36 T-CELL ENGAGING BISPECIFIC ANTIBODIES (T-BsAB)

T-cell engaging bispecific antibodies (T-BsAb) targeting CD20, a receptor on mature B lymphocytes

FOR EDUCATIONAL PURPOSES ONLY 38 Cytotoxic (CD8+) T cell releases cytotoxic granules leading to apoptosis of the targeted tumor cell

FOR EDUCATIONAL PURPOSES ONLY 39 Apoptosis of malignant B cell

FOR EDUCATIONAL PURPOSES ONLY 40 T-cell engaging bispecific antibodies (T-BsAb)

CD20 staining: Baseline After Treatment

Bargou R et al. Science. 2008;321:974-7

FOR EDUCATIONAL PURPOSES ONLY 41 Only one T-cell-engaging antibody approved by FDA

FOR EDUCATIONAL PURPOSES ONLY 42 T-cell recruiting bispecific antibodies

Wu Z, Cheung NV. Pharmacol Ther. 2018;182:161-175

FOR EDUCATIONAL PURPOSES ONLY 43 Development overview of T-BsAb

Wu Z, Cheung NV. Pharmacol Ther. 2018;182:161-175

FOR EDUCATIONAL PURPOSES ONLY 44 PREVENTATIVE CANCER VACCINES

A 3D model of the human papillomaviruses virus. Credit: Dr Microbe/iStock The Nobel Prize in Physiology or Medicine 2008 One half awarded to Harald zur Hausen "for his discovery of human papilloma viruses causing cervical cancer", the other half jointly to Françoise Barré-Sinoussi and Luc Montagnier "for their discovery of human immunodeficiency virus."

Harald zur Hausen

FOR EDUCATIONAL PURPOSES ONLY 46 Human papilloma virus (HPV) lifecycle

Graphic courtesy of The Nobel Foundation

FOR EDUCATIONAL PURPOSES ONLY 47 Preventative cancer vaccine(s) Two HPV vaccines approved by FDA (and throughout the world)

FOR EDUCATIONAL PURPOSES ONLY 48 HPV Vaccines Experience from Australia Both HPV and genital warts rapidly declined, largely thanks to herd immunity

Short-term impact of human papillomavirus (HPV) vaccination in Australia on anogenital warts cases (routine vaccination with or without catch-up): model predictions compared with empirical data. (A) Girls aged <21 years old (B) Boys aged <21 years old (C) Women aged 21–30 years old (D) Men aged 21–30 years old

J Infect Dis. 2017;216(10):1205-1209.

FOR EDUCATIONAL PURPOSES ONLY 49 Types of Cancer Immunotherapy (CIT)

Key to all forms of CIT: • Immune checkpoint blockade Effective antigen presentation • Dendritic cells and Therapeutic cancer vaccines •T-cell infiltration • Chimeric antigen receptor •Tumor killing via CTLs (CAR) T cells • T-cell recruiting bispecific antibodies • Preventative vaccines

FOR EDUCATIONAL PURPOSES ONLY 50 Science Magazine’s ‘Breakthrough or the Year’ in 2013 This year marks a turning point in cancer, as long- sought efforts to unleash the immune system against tumors are paying off—even if the future remains a question mark.

FOR EDUCATIONAL PURPOSES ONLY 51 Drolet M, Laprise JF, Brotherton JML, Donovan B, Fairley CK, Ali H, Bénard É, Martin D, Brisson M. The Impact of Human Papillomavirus Catch-Up Vaccination in Australia: Implications for Introduction of Multiple Age Cohort Vaccination and Postvaccination Data Interpretation. J Infect Dis. 2017 Dec 5;216(10):1205-1209. doi: 10.1093/infdis/jix476. PubMed PMID: 28968800; PubMed Central PMCID: PMC5853481

Thank you! Questions? [email protected] SOURCES AND PUBLICATIONS Source for overview and timeline multiple slides

Cancer Research Institute: Immunotherapy and timeline of progress: https://www.cancerresearch.org/immunotherapy/timeline-of-progress

FOR EDUCATIONAL PURPOSES ONLY Publications: Immune Checkpoint Inhibitors 1987: Brunet JF, Denizot F, Luciani MF, Roux-Dosseto M, Suzan M, Mattei MG, Golstein P. A new member of the immunoglobulin superfamily--CTLA-4. Nature 1987 Jul 16- 22; 328: 267-270. (PMID: 3496540) 1994: Uenaka A, Ono T, Akisawa T, Wada H, Yasuda T, Nakayama E. Identification of a unique antigen peptide pRL1 on BALB/c RL male 1 leukemia recognized by cytotoxic T lymphocytes and its relation to the Akt oncogene. J Exp Med 1994 Nov 1; 180: 1599-1607. (PMID: 7964448) 1996: Leach DR, Krummel MF, Allison JP. Enhancement of antitumor immunity by CTLA-4 blockade. Science 1996 Mar 22; 271: 1734-1736. (PMID: 8596936) 1999:Nishimura H, Nose M, Hiai H, Minato N, Honjo T. Development of lupus-like autoimmune diseases by disruption of the PD-1 gene encoding an ITIM motif-carrying immunoreceptor. Immunity 1999 Aug 11; 11: 141-151. (PMID: 10485649) Nishimura H, Okazaki T, Tanaka Y, Nakatini K, Hara M, Matsumori A, Sasayama S, Mizoguchi A, Hiai H, Minato N, Honjo T. Autoimmune dilated cardiomyopathy in PD-1 receptor-deficient mice. Science 2001 Jan 12; 291: 319-322. (PMID: 11209085) 2001: Tseng S-Y, Otsuji M, Gorski K, Huang X, Slansky JE, Pai SI, Shalabi A, Shin T, Pardoll DM, Tsuchiya H. B7-Dc, a new dendritic cell molecule with potent costimulatory properties for T cells. J Exp Med 2001 Apr 2; 193: 839-846. (PMID: 11283156) 2003: Hodi FS, Mihm MC, Soiffer RJ, Haluska FG, Butler M, Seiden MV, Davis T, Henry-Spires R, MacRae S, Willman A, Padera R, Jaklitsch MT, Shankar S, Chen TC, Korman A, Allison JP, Dranoff G. Biologic activity of cytotoxic T lymphocyte-associated antigen 4 antibody blockade in previously vaccinated metastatic melanoma and ovarian carcinoma patients. Proc Natl Acad Sci U S A 2003 Apr 15; 100: 4712-4717. (PMID: 12682289) 2010: Hodi FS, O'Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, Gonzalez R, Robert C, Schadendorf D, Hassel JC, Akerley W, van den Eertwegh AJ, Lutzky J, Lorigan P, Vaubel JM, Linette GP, Hogg D, Ottensmeier CH, Lebbé C, Peschel C, Quirt I, Clark JI, Wolchok JD, Weber JS, Tian J, Yellin MJ, Nichol GM, Hoos A, Urba WJ. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 2010 Aug 19; 363: 711-723. (PMID:20525992) Brahmer JR, Drake CG, Wollner I, Powderly JD, Picus J, Sharfman WH, Stankevich E, Pons A, Salay TM, McMiller TL, Gilson MM, Wang C, Selby M, Taube JM, Anders R, Chen L, Korman AJ, Pardoll DM, Lowy I, Topalian SL. Phase I study of single-agent anti-programmed death-1 (MDX-1106) in refractory solid tumors: safety, clinical activity, pharmacodynamics, and immunologic correlates. J Clin Oncol 2010 Jul 1; 28: 3167-3175. (PMID: 20516446)

FOR EDUCATIONAL PURPOSES ONLY

Publications: Dendritic cells and Therapeutic cancer vaccines 1992: Hunt DF, Henderson RA, Shabanowitz J, Sakaguchi K, Michel H, Sevilir N, Cox AL, Appella E, Engelhard VH. Characterization of peptides bound to the class I MHC molecule HLA-A2.1 by mass spectrometry. Science 1992 Mar 6; 255: 1261-1263. (PMID: 1546328) 1998: Naito Y, Saito K, Shiiba K, Ohuchi A, Saigenji K, Nagura H, Ontani H. CD8+ T cells infiltrated within cancer cell nests as a prognostic factor in human colorectal cancer. Cancer Res 1998 Aug 15; 58: 3491-3494. (PMID: 9721846) 2003: Zhang L, Conejo-Garcia JR, Katsaros D, Gimotty PA, Massobrio M, Regnani G, Makrigiannakis A, Gray H, Schlienger K, Liebman MN, Rubin SC, Coukos G. Intratumoral T cells, recurrence, and survival in epithelial ovarian cancer. N Engl J Med 2003 Jan 16; 348: 203-213. (PMID: 12529460) Hermans IF, Silk JD, Gileadi U, Salio M, Mathew B, Ritter G, Schmidt R, Harris AL, Old LJ, Cerundolo V. NKT cells enhance CD4+ and CD8+ T cell responses to soluble antigen in vivo through direct interaction with dendritic cells. J Immunol 2003 Nov 15; 171: 5140-5147. (PMID: 14607913) 2004: Hanada K, Yewdell JW, Yang JC. Immune recognition of a human renal cancer antigen through post-translational protein splicing. Nature 2004 Jan 15; 427: 252-256. (PMID: 14724640) Vigneron N, Stroobant V, Chapiro J, Ooms A, Degiovanni G, Morel S, van der Bruggen P, Boon T, Van den Eynde B. An antigenic peptide produced by peptide splicing in the proteasome. Science 2004 Apr 23; 304: 587-590. (PMID: 15001714) Warren EH, Vigneron NJ, Gavin MA, Coulie PG, Stroobant V, Dalet A, Tykodi SS, Xuereb SM, Mito JK, Riddell SR, Van den Eynde BJ. An antigen produced by splicing of noncontiguous peptides in the reverse order. Science 2006 Sep 8; 313: 1444-1447. (PMID: 16960008) 2005: Pagès F, Berger A, Camus M, Sanchez-Cabo F, Costes A, Molidor R, Mlecnik B, Kirilovsky A, Nilsson M, Damotte D, Meatchi T, Bruneval P, Cugenc P-H, Trajanoski Z, Fridman W-H, Galon J. Effector memory T cells, early metastasis, and survival in colorectal cancer. N Engl J Med 2005 Dec 22; 353: 2654. (PMID: 16371631)

Galon J, Costes A, Sanchez-Cabo F, Kirilovsky A, Mlecnik B, Lagorce-Pagès C, Tosolini M, Camus M, Berger A, Wind P, Zinzingohoué, Bruneval P, Cugenc P-H, Trajanoski Z, Fridman W-H, Pagès. Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science 2006 Sep 29; 313: 1960-1964. (PMID: 17008531) Speiser DE. Lienard D, Rufer N, Rubio-Godoy V, Rimoldi D, Lejeune F, Krieg AM, Cerottini JC, Romero P. Rapid and strong human CD8+ T cell responses to vaccination with peptide, IFA, and CpG oligodeoxynucleotide 7909. J Clin Invest 2005 Mar; 115: 739-746. (PMID: 15696196) Baumgaertner P, Jandus C, Rivals JP, Derre L, Lovgren T, Baitsch L, Guillaume P, Luescher IF, Berthod G, Matter M, Rufer N, Michielin O, Speiser DE. Vaccination-induced functional competence of circulating human tumor-specific CD8 T-cells. Int J Cancer 2011 Jul 27. (PMID: 21796616) 2009: Morales A, Phadke K, Steinhoff G. Intravesical mycobacterial cell wall-DNA complex in the treatment of carcinoma in situ of the bladder after standard intravesical therapy has failed. J Urol 2009 Mar; 181:1040-1044. (PMID: 19150551) 2010: Kantoff PW, Higano CS, Shore ND, Berger ER, Small EJ, Penson DF, Redfern CH, Ferrari AC, Dreicer R, Sims RB, Xu Y, Frohlich MW, Schellhammer PF; IMPACT Study Investigators. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med 2010 Jul 29; 363: 411-422. (PMID: 20818862) 2011: Schwartzentruber DJ, Lawson DH, Richards JM, Conry RM, Miller DM, Treisman J, Gailani F, Riley L, Conlon K, Pockaj B, Kendra KL, White RL, Gonzalez R, Kuzel TM, Curti B, Leming PD, Whitman ED, Balkissoon J, Reintgen DS, Kaufman H, Marincola FM, Merino MJ, Rosenberg SA, Choyke P, Vena D, Hwu P. gp100 peptide vaccine and interleukin-2 in patients with advanced melanoma. N Engl J Med 2011 Jun 2; 364: 2119-2127. (PMID: 21631324) Butler MO, Friedlander P, Milstein MI, Mooney MM, Metzler G, Murray AP, Tanaka M, Berezovskaya A, Imataki O, Drury L, Brennan L, Flavin M, Neuberg D, Stevenson K, Lawrence D, Hodi FS, Velazquez EF, Jaklitsch MT, Russell SE, Mihm M, Nadler LM, Hirano N. Establishment of antitumor memory in humans using in vitro-educated CD8+ T cells. Sci Transl Med 2011 Apr 27; 3: 80ra34. (PMID: 21525398)

FOR EDUCATIONAL PURPOSES ONLY

Publications: Chimeric antigen receptor (CAR) T cells

1992: Novak TJ, Yoshimura FK, Rothenberg EV. In vitro transfection of fresh thymocytes and T cells shows subset-specific expression of viral promoters. Mol Cell Biol. 1992 Apr;12(4):1515- 27. PubMed PMID: 1312665; PubMed Central PMCID: PMC369593 1993: Brocker T, Peter A, Traunecker A, Karjalainen K. New simplified molecular design for functional T cell receptor. Eur J Immunol. 1993 Jul;23(7):1435-9. PubMed PMID: 8325320 2002: Dudley ME, Wunderlich JR, Robbins PF, Yang JC, Hwu P, Schwartzentruber DJ, Topalian SL, Sherry R, Restifo NP, Hubicki AM, Robinson MR, Raffeld M, Duray P, Seipp CA, Rogers-Freezer L, Morton KE, Mavroukakis SA, White DE, Rosenberg SA. Cancer regression and autoimmunity in patients after clonal repopulation with antitumor lymphocytes. Science. 2002 Oct 25;298(5594):850-4. Epub 2002 Sep 19. PMID: 12242449; PMCID: PMC1764179 Maher J, Brentjens RJ, Gunset G, Rivière I, Sadelain M. Human T-lymphocyte cytotoxicity and proliferation directed by a single chimeric TCRzeta /CD28 receptor. Nat Biotechnol. 2002 Jan;20(1):70-5. PubMed PMID: 11753365 2003: Otero DC, Anzelon AN, Rickert RC. CD19 function in early and late B cell development: I. Maintenance of follicular and marginal zone B cells requires CD19-dependent survival signals. J Immunol. 2003 Jan 1;170(1):73-83. PMID: 12496385 2004: Imai C, Mihara K, Andreansky M, Nicholson IC, Pui CH, Geiger TL, Campana D. Chimeric receptors with 4-1BB signaling capacity provoke potent cytotoxicity against acute lymphoblastic leukemia. Leukemia. 2004 Apr;18(4):676-84. PMID: 14961035. 2006: Morgan RA, Dudley ME, Wunderlich JR, Hughes MS, Yang JC, Sherry RM, Royal RE, Topalian SL, Kammula US, Restifo NP, Zheng Z, Nahvi A, de Vries CR, Rogers-Freezer LJ, Mavroukakis SA, Rosenberg SA. Cancer regression in patients after transfer of genetically engineered lymphocytes. Science 2006 Oct 6; 314: 126-129. (PMID: 16946036) 2007: Michael C. Jensen, Leslie Popplewell, David DiGiusto, Michael Kalos, Andrew Raubitschek, and Stephen J. Forman. A First-In-Human Clinical Trial of Adoptive Therapy Using CD19- Specific Chimeric Antigen Receptor Re-Directed T-Cells for Recurrent/Refractory Follicular Lymphoma. Blood 2007 110:288 2008: Till B, Jensen MC, Wang J, Chen EY, Wood BL, Greisman HA, Qian X, James SE, Raubitschek A, Forman SJ, Gopal AK, Pagel JM, Lindgren CG, Greenberg PD, Riddell SR, Press OW. Adoptive immunotherapy for indolent non-Hodgkin lymphoma and mantle cell lymphoma using genetically modified autologous CD20-specific T cells. Blood 2008 Sep 15; 112: 2261- 2271. (PMID: 18509084) 2011: Kalos M, Levine BL, Porter DL, Katz S, Grupp SA, Bagg A, June CH. T cells with chimeric antigen receptors have potent antitumor effects and can establish memory in patients with advanced leukemia. Sci Transl Med 2011 Aug 10; 3: 95ra73. (PMID: 21832238) Porter DL, Levine BL, Kalos M, Bagg A, June CH. Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia. N Engl J Med 2011 Aug 25; 365: 725-33. Epub 2011 Aug 10. (PMID: 21830940) 2013: Brentjens RJ1, Davila ML, Riviere I, Park J, Wang X, Cowell LG, Bartido S, Stefanski J, Taylor C, Olszewska M, Borquez-Ojeda O, Qu J, Wasielewska T, He Q, Bernal Y, Rijo IV, Hedvat C, Kobos R, Curran K, Steinherz P, Jurcic J, Rosenblat T, Maslak P, Frattini M, Sadelain M. CD19-targeted T cells rapidly induce molecular remissions in adults with chemotherapy- refractory acute lymphoblastic leukemia. Sci Transl Med 2013 Mar 20; 5 (177): 177ra38. (PMID: 23515080)

FOR EDUCATIONAL PURPOSES ONLY

Publications: T-cell engaging bispecific antibodies (T-BsAb)

2008: Bargou R, Leo E, Zugmaier G, Klinger M, Goebeler M, Knop S, Noppeney R, Viardot A, Hess G, Schuler M, Einsele H, Brandl C, Wolf A, Kirchinger P, Klappers P, Schmidt M, Riethmüller G, Reinhardt C, Baeuerle PA, Kufer P. Tumor regression in cancer patients by very low doses of a T cell-engaging antibody. Science. 2008 Aug 15;321(5891):974-7. doi: 10.1126/science.1158545. PubMed PMID: 18703743.

2018: Wu Z, Cheung NV. T cell engaging bispecific antibody (T-BsAb): From technology to therapeutics. Pharmacol Ther. 2018 Feb;182:161-175. doi: 10.1016/j.pharmthera.2017.08.005. Epub 2017 Aug 20. Review. PubMed PMID: 28834699; PubMed Central PMCID: PMC5785550.

FOR EDUCATIONAL PURPOSES ONLY Publications: Preventative Cancer Vaccines

1983: Durst M, Gissmann L, Ikenberg H, zur Hausen H. A papillomavirus DNA from a cervical carcinoma and its prevalence in cancer biopsy samples from different geographic regions. Proc Natl Acad Sci U S A 1983 June; 80: 3812-3815. (PMID: 6304740)

2017: Drolet M, Laprise JF, Brotherton JML, Donovan B, Fairley CK, Ali H, Bénard É, Martin D, Brisson M. The Impact of Human Papillomavirus Catch-Up Vaccination in Australia: Implications for Introduction of Multiple Age Cohort Vaccination and Postvaccination Data Interpretation. J Infect Dis. 2017 Dec 5;216(10):1205-1209. doi: 10.1093/infdis/jix476. PubMed PMID: 28968800; PubMed Central PMCID: PMC5853481.

FOR EDUCATIONAL PURPOSES ONLY