HCC Immunotherapy Yukai He Medical College of Georgia Augusta University 9222019 ILCA Chicago Disclosure My employer Medical College of Georgia holds the patents of TCRs and CARs Consultant CBMG Cupertino CA ID: 908982
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Engineering T cells for HCC Immunotherapy
Yukai He Medical College of Georgia, Augusta University
9-22-2019, ILCA, Chicago
Slide2DisclosureMy employer, Medical College of Georgia, holds the patents of TCRs and CARs
Consultant: CBMG, Cupertino, CA
Slide3Recruiting a highly motivated postdoc with immunology background
Slide4Cancer vaccines: Not effective yet. a. Together
with ACT b. Neoantigen cancer vaccinesCheckpoint blockade effective in ~20% of patients (El-Khoueiry et al, 2017, Lancet) - Checkpoint blockade plus anti- angiogenesis, 30-40% response rateEngineered T cells therapy are emerging Immunotherapy for HCC
Slide5HCC
ACTCAR-T
TC
R-T
Zhu et al, 2018
Developing novel GPC3
mAbs
and novel CAR-Ts
Hong et al, 2014
Cancer Vaccines
Oncolytic virus in situ vaccines
Slide6Identify TCRs for HCC immunotherapy
Slide7TCR
Slide8Lentivector prime & peptide boost induce a high level of AFP-specific T cells
Peptide Boost Peptide Trivax iv Peptides PolyIC Anti-CD40 AbLentivector PrimeHLA Tg miceAFP-lv
Yibing
Peng
Slide9Splenocytes from immunized mice
HepG2Splenocytes (2 million AFP Tet+ T cells)The therapeutic potential of adoptive transfer of AFP-specific T cells
2cm
Slide10This population cells must have the TCR that recognize human HCC tumor cells
TCR
Slide11Identification of TCRs:Via T cell hybridoma technique
Maintain the diversity of T cell repertoireDetermine TCR affinity before cloningIdentify and clone the paired TCR α and β chainsNine (9) unique TCRs specific for AFP158 epitope, the most frequently presented epitope were identified.TCRs have different affinity.Wei Zhu
Slide12Slide13No mispairing with endogenous human TCR
Slide14Specifically recognize AFP+ HLA-A2 HCC tumor cells
Slide15Adoptive transfer of human TCR-T generates antitumor effect against HCC xenografts in NSG mice
Slide16Slide17Summary I:1.
9 TCRs with different affinity2. Potent antitumor effects in preclinical models.3. Wrapping up the cross-reactivity studyA. On-target/off-tumorB. Off-targetC. AlloreactivityTCRs have different affinity, antitumor effects and cross-reactivity. Selected 1-2 TCR with no cross-reactivity with normal human cells
Slide18GPC3-specific CAR-Ts
Slide19CARTs for HCCGPC3-specific CARTsGC33 antibodyYP7, HN3 antibodies
MHC/AFP158-specific CARTsIntracellular antigenMHC-restricted
Slide20(524-563)
YP7HN3(14 Carbon chainGPC3 structure and antibodiesAdopted from Ho M, Kim H. 2011 And Haruyama Y, Kataoka H. 2016
Slide21Developing novel GPC3-specific CART for HCC immunotherapy
Develop GPC3-specific antibodiesA. 20 mAbsB. 14 of them can also bind to GPC3+ tumor cellsCreate CAR-T cells Dr. Xiaotao Jiang
Slide221. Develop GPC3-specific antibodies
Slide23Slide24Slide25Slide26Slide27Slide28Slide29Soluble GPC3 does not activate CARTs, nor inhibit the killing of GPC3+ tumor cells
Slide30Slide31Slide32Summary II1. Develop 3 hGPC3-specific and HCC-specific mAbs (6G11, 8F8, and 12D7
).2. Create 3 corresponding CARTs from the 3 mAbs, which expand after HCC cell stimulation.3. The 6G11 and 8F8 CARTs targeting hGPC3 N- or C- epitope have strong effector function.4. Adoptive transfer of 6G11 and 8F8, but not 12D7 CARTs results in tumor regression.
Slide33Slide34AcknowledgementYukai’s lab: Yibing Peng Leidy Caraballo Galva
Catherine CaiYanxia ShaoPrevious membersQi LiDr. Xiaotao JiangDr. Wei ZhuDr. Lan WangDr. Yuan HongCollaborators: Dr. Esteban CelisDr. Ignatowicz (Georgia State University)Georgetown UniversityDr. Aiwu (Ruth) He Funding: NCI R01 CA168912, NCI R01 CA235159Georgia Cancer Center intramural grant
Slide35HCC is an increasing problem in USA
In US, the HCC incidence rate increases the fastest, has doubled in 20 years, mainly due to non-viral factors.Worldwide, HCC is the 6th most common cancer, 850,000 cases.Few drugs are available with limited efficacy. HCC is the 2nd leading cause of cancer death among man (>600,000).
Slide36Nature Made
Man MadeTCRCAR
Slide37