Cliona Rooney (Baylor College of Medicine, USA)
“Cancer Immunotherapy and Challenges for NPC”
- T cell for each patient, pre existing , 22% chance response
- Vaccine an Ad-based LMP2, MVA-EBNA1-LMP2
- LCL activated vEBVST
- Singpore TESSA therapeutics (http://goo.gl/zdbYpA) 330 patients (與Wed Poster #5相關)
- Ad LMP1/2/LCL activated T cell for NPC, not better for EBVST, but is better in lymphoma patients (type 2 malignancy lymphoma)
- SFC, IFNG coated plate, 6 month 1.5 year
- survivors epitome spread: MAGEA4 + SURVIVIN + PRAME
- Dendritic cells are difficult to make in NPC patients
- 1st stimulation: EBV EBNA1 ,LMP1, LMP2, BARF1
- 2nd stimulation: Pepmix all possible MHC2
- GRACE trial (patients of lymphoma)
- Switch to IL15/7
- High dose IL15 increase specificity
- Fewer CD4 cells in high dose IL15 (SF: IL21 and IL15 are part of the gamma-chain cytokine family and are crucial for survival and proliferation of Tfh (follicular Th), cytotoxic and memory T cells, both IL21 and IL15 are being used in clinical trial)
- IL15H increases central key EBVSTs
- Post infusion expansion of EBVSTs in patients with lymphoma
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heterogeneity in NPC TME
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Importance for epitope spreading, maybe viral lytic genes are important (Mei-Ru asked what kind of lytic genes in her mind, she replied: IE genes)
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TGFBR
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Infiltrating barrier
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Gottschalk PI is responsible
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Lympho depletion/Reactivate EBV
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Immuno checkpoint
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Genetic TGFBR DN to increase T cells
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Steve Rosenberg was mentioned again and again and again (https://goo.gl/LKXqYG)
- T cells express NPC expressing cytokine 2 receptor to “homing”
- GuangZhou published some promising results (ref: Oncoimmunology 2015)
From Ming-Han
- 1 Small molecules? (one drug for all patients)
- 2 EBV-specific T cells;
- 3 Chimeric antigen receptor (CAR) T cells?
- 4 Gene-modified T cells? (EBVSTs)
- One patient one drugs?
Ongoing trials
- Chiun Hsu (許駿); NTU PD1 inhibitor (KEYTZUDA KEYNOTE 028 Overall Response rate 10.8 %)
- LMP2 peptide pulsed DCs (HK): increase LMP2A specific T cells
- Ad-dLMP1-LMP2 transduced DCs (Singapore by Prof. Toh): DTH but no elevated LMP specific T cells.
- MVA-EBNA1-LMP2: functional in 50% patients with the elevated T cell responses.
- LCL-activated EBVSTs for NPC (adjuvant (62%) remain diseases free / 2nd or relapse in 48.7%)
- LCL activated EBVSTs after Chemotherapy? (Singapore (Toh, Ho): 35 patients; 97% type III diseases; Gemicitabin and carboplatin 4 cycles. (combine treatment?); 71.4% responses; overall survival 2yr 65%; 5yr 35%.)
- Gemicibin alone vs Gemicibin + EBVSTs on going in 350 patients. (Ongoing)
Ad5f35-∆LMP1-LMP2 (Adenovim)
- infect PBMC –> boosted by EBV-LCLs (in between plus IL2) —> wish to have LMP2A/1 T cell CTLs. (Bollard et al, J, Clin Onco 2014 32 (8) 798-808.)
EBVST treat for EBV lymphoma (CTC project)
to NKT lymphoma (remission 25/26)
– Epitope spreading after treatment of EBVSTs seems very important.
This strategy seems good BUT problems
- too long
- No LCL available from these EBV+lymphoma patients; either low B cell or the B cells can’t be immortalised by EBV for?? reason.
- Require live virus.
- Many cases all T cells only in the end recognise EBNA3C.
Original plan:
- (PBMC infected by B95-8) –> LCL –> stimulated with DCs with LMP1/2A ––> T cells (peptide of LMP2A by using many many peptides; each 15mer but with 11aa overlapping each)
Now:
- PBMC+peptide –> (+IL4/7) can have expansion 100X times T cells only within 10 days; enough time to treat PTLD.
Issue:
- This strategy works super well in healthy donor BUT IL4/7 doesn’t work well for expansion of patient’s T cell for ?? reason.
Phase I clinical trial design (GRACE)
- HL, BL… EBV+ lymphoma.
- Patients T cells with very low avidity;
- Patient with lymphoma have very few T cells.
- Growth of T cells from patients always badly.
New strategy:
IL4/7 vs IL7/15? which is better:
found IL7/15 is better (high dose IL15: 100ng/ml; medium dose IL15: ? ng/ml)
But still IL7/15 still difficult to expand T cells from patients.
IL4+IL7 IL7+IL15 IL7+IL15hi
CD4 50% 30% ~0
CD8 50% 70% ~100 %
Problem2: LMP1/2 actually not expressed in all tumor cells. For example; if stimulate T cells with BARF1, LMP2, EBNA1 or LMP1, in the end T cells only recognise one peptides…
Epitope spreading:
- SSX2, NYESP, Survivin, Prame, Mage4 —> these antigens only exists in lymphoma.
- after treatment patients have T cells against these peptides then the treatments outcome will be better.
- So far: 2/10 cases total cure; 4/10 with better response.
For NPC cases:
- EBVSTs have less responses for NPC patients
- Possible reasons: solid tumor; difficult for T cells to enter; Immune suppressive environment.
Requirements if want to treat NPC:
- migration to tumor site
- Infiltrate tumor parenchtmas?
- have to proliferate at tumor sites that express also MHCI
@Gottschalk (NPC clinical trials)
@Effective CAR and TIL stimulation
Requirement for human trials: GMP director; CMP CTL; everything GMP
——————————–Q1: CD4/8 mix during T cell expansion; which one is better?
Q2: Epitope spreading: spreading to cancer-associating T cells with viral antigens?
A2: not viral antigens.
Q3: LCL or peptide to stimulate T cells? why difference?
A3: use bacteria or baculovirus to stimulate? Different method might lose the chance to have correct epitopes; for example, phosphorylation. Now we don’t use LCL to stimulate T cells; we use adenovirus-infected DCs it’s better.
Q5: someone firstly transgene the T cells with specific chemokine receptor corresponding to chemokines secreted by tumor cells; is that good? Yes.
Q6: Combine EBVSTs with chemotherapy? which first?
A6: Suggest to firstly to irradiation or chemotherapy then inject T cells since tumor necrosis can attract T cells to the tumor sites.
In EBV Meeting Invited lecture on immunology, Plenary lecture hall KOH-B-10
Chairperson: Cliona Rooney, Baylor College of Medicine, Houston, USA
Lecturer: Jeffrey Cohen, National Institutes of Allergy and Infectious Diseases