CANCER IMMUNOTHERAPY · 2018-11-05 · CANCER IMMUNOTHERAPY OVERVIEW OF CURRENT LANDSCAPE 2018 AMWA...

CANCER IMMUNOTHERAPY OVERVIEW OF CURRENT LANDSCAPE

2018 AMWA Annual Meeting

1 November 2018

Petra Volna, Senior Regulatory Documentation Scientist Genentech Inc.

2 2

When Was Cancer Immunotherapy First Used?

Hint: The answer may surprise you

FOR EDUCATIONAL PURPOSES ONLY

3 3

William B. Coley, MD: The Father of Immunotherapy


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

4 FOR EDUCATIONAL PURPOSES ONLY

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

Maturation in situ

Early

Intermediate

Late

Dendritic cells (DCs) have the

unique capacity to initiate primary

and secondary immune responses


Pierre P. et al. Nature. 1997;388:787-92

7

Discovery of T-cell Growth Factor (Interleukin-2)

Gillian M Griffiths, Cambridge Immunology Network

University of Cambridge


Electron Microscopy Facility at The National Cancer Institute

at Frederick (NCI-Frederick)

T-cell-mediated Cytotoxicity against Autologous

Malignant Melanoma

8

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


Binding of immunogenic peptides to

Ia histocompatibility molecules


10

Immunological Synapse Created

Gillian M Griffiths, Cambridge Immunology Network

University of Cambridge


11 11

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


CANCER-IMMUNE EQUILIBRIUM

13

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


14

Antigen release

Antigen presentation

(dendritic cells/APCs)

Priming and activation

(APCs and T cells) T-cell trafficking

T-cell infiltration

(T cells and endothelial cells)

T-cell recognition

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

Cancer Immunity Cycle and Immune Phenotypes


15

Types of Cancer Immunotherapy (CIT)

• Immune checkpoint blockade

• Dendritic cells and Therapeutic cancer vaccines

• Chimeric antigen receptor (CAR) T cells

• T-cell recruiting bispecific antibodies

• Preventative vaccines

Key to all forms of CIT: Effective antigen presentation

•T-cell infiltration

•Tumor killing via CTLs


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."

James P. Allison Tasuku Honjo

Discovery of PD-1 and

its importance for

cancer therapy

PD-1 is a protein

expressed on the

surface of T cells that

functions as a T-cell

brake

One of several scientists

who had made the

observation that CTLA-4

functions as a brake on

T cells

Investigated CTLA-4

blockade to disengage

the T-cell brake and

unleash the immune

system to attack cancer

cells


18

Immune Checkpoint Inhibitors


2000 2015 2005 1995 2010

1994

CTLA-4 identified as negative

regulator of T-cell activation

1996

CTLA-4 blockade could

cause tumor rejection

in mice

2010

Improved survival with ipilimumab,

CTLA-4-specific antibody, in

patients with metastatic melanoma

2011

FDA approves Yervoy, ipilimumab,

for advanced melanoma

1999

PD-1 Identified as

immune checkpoint

2003

CTLA-4-specific antibody

induces clinical

regressions in patients

with advanced melanoma

2001

B7-H1 (PD-L1) and B7-DC (PD-L2)

identified as ligands for PD-1 2010

PD-1-specific antibody, induces

frequent tumor regressions in

patients with advanced melanoma,

renal, lung and colon cancer

2014

Opdivo, nivolumab, a PD-1-specific

antibody approved in Japan for

advanced melanoma

2014

FDA approves Keytruda,

pembrolizumab, for advanced

melanoma

2015

FDA approves Tecentriq,

atezolizumab, for bladder

cancer

2012

Anti-PD-1 antibody shows dramatic

efficacy results in Ph 1 trial

How Do Immune Checkpoint Inhibitors Work?

Antibodies against PD-1 inhibit

the function of the brake

leading to activation of T cells

and highly efficient attack on

cancer cells.

Activation of T cells requires

that the T-cell receptor binds

to structures on other

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

CTLA-4 block the function of

the brake leading to activation

of T cells and attack on cancer

cells.

PD-1 is another T-cell

brake that inhibits T-cell

activation


Graphic courtesy of The Nobel Foundation

20

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

21

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


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


DENDRITIC CELLS AND THERAPEUTIC CANCER VACCINES

Magnification 16,000x. (Rita Serda/FEI Image)

24

Dendritic cells and Therapeutic cancer vaccines


2000 2005 2010

2011

Peptide vaccine + IL-2 improves

melanoma responses

1998

A landmark study showed

that accumulation of CD8+ T

cells within the tumor (TILs)

predicted improved patient

survival 2011

Artificial antigen presenting cells

(aAPC) could successfully

enhance adoptive therapy of tumor

antigen-specific CD8+ T cells

2010

FDA approves the use of

sipuleucel-T (Provenge®) for the

treatment of prostate cancer

2003

NKT cells enhance CD4+ and

CD8+ T cell responses to soluble

antigen in vivo through direct

interaction with dendritic cells

2003

First data indicating that

presence of tumor-infiltrating

lymphocytes in the primary

tumor strongly correlated with

patient survival

2005

Type, density, and location of immune cells

within tumor samples found to be a better

predictor of patient survival than previous

pathological criteria for tumor staging

2005

Rapid and strong human CD8+ T cell

responses to vaccination with peptide, IFA,

and CpG oligodeoxynucleotide

1992

First characterization of

peptides from MHC class I

2004

The first tumor antigenic

peptides produced by

peptide splicing reported

2009

Mycobacterial cell wall-DNA

complex showed antineoplastic

activity in patients with bladder

cancer

Personalized Vaccines for Cancer Immunotherapy Customizing a patient-specific cancer vaccine

25

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

Published by AAAS


Neoepitope Vaccines Promote a Functional Cancer

Immunity Cycle

26



Personalized Cancer Medicine



The Interconnected Dimensions of Cancer Heterogeneity



Source: Sahin, U. et al. Nature 547, 222–226 (2017)

CHIMERIC ANTIGEN RECEPTOR (CAR) T CELLS

Magnification 16,000x. (Rita Serda/FEI Image)

Meletios Verras / Getty Images

32

Chimeric antigen receptor (CAR) T cells

2015 2005 1995 2010

1992

Primary T-cell engineering

1993

First generation of CARs

(CD3ζ-based)

2007

First IND for CD19 CAR

therapy (BB-IND#11411)

2002

In vitro-expanded T cells can cause

tumor regressions in advanced

melanoma

2011

New CAR T cell treatment

cures patients with CLL

2017

FDA approves CD19 CAR

T therapy for pediatric ALL

and NHL

2013

CAR T cell therapy

attains complete

responses in ALL

2011

Adoptive immunotherapy with CD8+

T cells genetically engineering to

recognize the NY-ESO-1 induce

remissions in sarcoma and

melanoma


2002

Second generation of CARs

(CD28-based)

2003

Demonstration of CD19

as a valid target for CARs

2006

Bulk T cells transduced with T cell

receptor genes are used to treat

patients with melanoma

2004

Third generation of CARs

(4-1BB-based)

2008

CAR T cells induce

clinical responses

in patients with

B cell lymphomas

33

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


34

CAR-T Cell Therapy Is Associated with Cytokine

Release Syndrome and Neurotoxicity



Published by AAAS

35

Conditionally Expressed CAR using Notch as a Signal

Induction and Response Pathway System



Published by AAAS

36

Regional disparities in studies of CAR T cell therapies



Published by AAAS

T-CELL ENGAGING BISPECIFIC ANTIBODIES (T-BsAB)

38

T-cell engaging bispecific antibodies (T-BsAb)

targeting CD20, a receptor on mature B lymphocytes


39

Cytotoxic (CD8+) T cell releases cytotoxic granules

leading to apoptosis of the targeted tumor cell


40

Apoptosis of malignant B cell


41

T-cell engaging bispecific antibodies (T-BsAb)


Baseline After Treatment CD20 staining:

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

42

Only one T-cell-engaging antibody approved by FDA


43

T-cell recruiting bispecific antibodies


Wu Z, Cheung NV. Pharmacol

Ther. 2018;182:161-175

44

Development overview of T-BsAb


Wu Z, Cheung NV. Pharmacol Ther.

2018;182:161-175

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

Human papilloma virus (HPV) lifecycle


Graphic courtesy of The Nobel Foundation

Preventative cancer vaccine(s) Two HPV vaccines approved by FDA (and throughout the world)


HPV Vaccines Experience from Australia Both HPV and genital warts rapidly declined, largely thanks to herd immunity


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

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

50

Types of Cancer Immunotherapy (CIT)

• Immune checkpoint blockade

• Dendritic cells and Therapeutic cancer vaccines

• Chimeric antigen receptor (CAR) T cells

• T-cell recruiting bispecific antibodies

• Preventative vaccines

Key to all forms of CIT: Effective antigen presentation

•T-cell infiltration

•Tumor killing via CTLs


51

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.

Thank you!

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

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


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)


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)


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)


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.


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.


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