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Facilitating T-cell therapy in solid
tumors with oncolytic adenovirus
Joao Santos1,2, Mikko Siurala1,2, Riikka Havunen1,2, Victor Cervera-Carrascon1,2,
Suvi Sorsa1, Akseli Hemminki1,2,3
1TILT Biotherapeutics Ltd, Helsinki, Finland;´2Cancer Gene Therapy Group, Department of Oncology, Faculty of
Medicine, University of Helsinki, Helsinki, Finland; 3Helsinki University Hospital Comprehensive Cancer Center,
Helsinki, Finland.
Background
Conclusions
Results1. Adenovirus coding for TNFa and IL-2
improves the B16.OVA growth control in
combination with OT-I cell therapy1
• Tumor-infiltrating lymphocyte (TIL) or gene-engineered T-cell
therapy have efficacy limitations such as suboptimal trafficking
of transferred cells to tumors
• Lymphodepleting preconditioning and high-dose IL-2
postconditioning are major sources of toxicity in adoptive
T-cell therapy protocols
• Programmed Death (PD)-1 blockade therapy demonstrates
good clinical results in only in TIL infiltrated tumors
• TILT-123 (Ad5/3-E2F-D24-hTNFa-IRES-hIL2) is an oncolytic
virus designed to enable T-cell therapy coding for:
• Human Tumor Necrosis Factor alpha (TNFa)
– Increases T-cell trafficking
• Human interleukin-2 (IL-2) – Increases T-cell
survival and growth
2. TILT-123 enables complete tumor
regression and protection from tumor
rechallenge in TIL treated hamsters2
6. Prime & boost adenovirus therapy
regimen enables 100% survival in
anti-PD-1 treated mice6
5. TILT-123 improves the survival and
efficacy of animals treated with adoptive
T-cell transfer without preconditioning5
4. Adenovirus-mediated local IL-2
delivery is superior to postconditioning
with systemic high-dose IL-24
3. TILT-123 leads to regression and
transduction of distant tumors in a
TIL therapy setting3
(A) HapT1 tumor-bearing hamsters were treated 5 times with 1 × 109 VPs of TILT-123 and once with
4×106 TILs both injected i.t. (n = 6–7). (B) Complete tumor remission was evaluated before animals
were euthanized. (C) Hamsters previously cured of HapT1 tumors were re-challenged with the same
HapT1 tumor cells or (D) with a distinct cell line (DDT1-MF2).
(A) Combined adenoviruses coding for mTNFa and mIL2 (1:1 ratio) were used to treat B16.OVA tumors in
combination with adoptive transfer of 1.5×106 CD8-enriched OT-I cells. (B) B16.OVA tumor-bearing mice were
administered 6 × 106 111Indium-oxine labeled OT-I cells intraperitoneally (i.p.) with simultaneous intratumoral
(i.t.)injection of cytokine-coding adenoviruses. Mice were imaged on 24, 48, and 96 hours after treatment
through SPECT/CT. (C) Representative SPECT/CT images of 96 hours timepoint with white circles indicating
the locations of subcutaneous tumors.
Hamsters bearing 2 HapT1 tumors were infused with 5x107 TILs
received 5 injections of 1x108 VPs of TILT-123 i.t. (A) The growth of
injected and (B) non-injected hamster tumors (n=5-6) was measured
every two to three days until day 33. (C) Small amounts of viral DNA
was detectable also in non-injected tumors on day 16. (D) No
differences were observed between the injected and non-injected
tumor sizes on day 33.
(A) 1 × 106 OT-I cells were infused in B16.OVA tumor-bearing mice that were treated 5 + 5 days during a period
of 12 days with mIL‐2 (100,000 IU) i.p. or once a week with 1 × 108 vp of Ad5‐CMV‐mIL‐2 i.t. (n=7-9). (B)
Levels of mIL‐2 were measured from end‐point tumors and serums with cytometric bead array.
(A) HapT1 tumor-bearing hamsters received 5x107 TILs i.p. and 4 rounds of 5 injections of 1x108 VPs of
TILT-123 intratumorally and/or lymphodepleting preconditioning. Survival was followed during 121 days
(n=4-5). (B) Mice tumor growth followed during 11 days (n=7-10).
(A) Combined adenoviruses coding for mTNFa and mIL2 (1:1 ratio) were used to treat B16.OVA tumors in
combination with i.p. administration of 0.1 mg of anti-PD-1 (repeated every 3 days for a total of 13–15 times)
(n=12-16). (B) Overall survival. (C) Individual tumor growth lines for the different conditions tested.
References
TILT-123 viral particles (VPs) transduce and lyse tumor cells releasing TNFa, IL-2 and danger signals in the
tumor microenvironment. This will activate and attract TILs to the tumor site that were either adoptively
transferred or potentiated through inhibition of the PD-1 pathway. Consequently, the efficacy of adoptive T-cell
or anti-PD-1 therapy will be enhanced.
D.C.
A. B. C.
A. B.
A.
A. B.
A. B.
C.
TILT Biotherapeutics Ltd
Haartmaninkatu 3, 4th floor, C-wing
00290 Helsinki, Finland
For more information:
• Adenovirus-mediated delivery of TNFa and IL-2
enables adoptive T-cell therapy using TIL therapy or
gene-modified T-cells
• TILT-123 induces systemic antitumor responses and
tumor-specific memory in animals treated with TIL
therapy
• TILT-123 replaces high-dose IL-2 postconditioning
and lymphodepleting preconditioning in a setting of
adoptive T-cell therapy
• Adenovirus therapy enables complete responses in
animals receving anti-PD-1 therapy
• Clinical translation is underway to validate these
hypotheses
™
A. B.
1Siurala M. et al; Mol Ther (2016)2Havunen R. et al; Mol Ther Onc (2017)3Havunen R. et al; Submitted4Santos JM. et al; Int J Cancer (2017)5Santos JM. et al; Submitted6Cervera-Carrascon V. et al; Oncoimmunology (2017)
D.
B.
C.