Product and Pipeline

More effective combination treatments for cancer

Cancers are complex dynamic and adaptive diseases with the tumor micro-environment comprising many different cell types, matrix proteins and secreted molecules.

The interplay between these elements impacts the responsiveness to therapy and whether there is continued tumor survival and progression, even in the face of continued treatments. We believe that remodelling of the tumor microenvironment and taking a multi-pathway and multi-target approach offers an opportunity to significantly improving response rates and durability of response.

Onco-Dermatology Pipeline addressing Multiple BCC Indications

Pipeline – Stage of Development

Product Indication Preclinical Phase 1 Phase 2 Phase 3 Status
SP-002: Phase 2A Multi-lesional Basal Cell Carcinoma
Study closed (Topline data in 2H, 2024)
SP-002: Phase 2B Locally Advanced BCC (combination regimen)
Study recruiting
SP-002: Phase 1/2A H&N Squamous Cell Carcinoma (combination regimen)
Commence in 1H, 20251
SP-105 Clinical Trial enabling studies
On-going CTN enabling studies
SP-500: Platform Preclinical evaluation

1 Subject to funding

about to commence
on-going studies


SP-002 is a human adenovirus 5 vector encoding Interferon-γ

SP-002 is an adenoviral vector (serotype 5, Ad5) encoding the therapeutic cytokine Interferon-γ. The vector has been engineered to be replication-deficient so it can transduce cells and produce Interferon-γ but not new viral particles (a safety feature not present in oncolytic viruses, which may also replicate in non-cancer cells). Interferon-γ has shown superior potency against tumors compared with Interferon-⍺, however, its successful clinical application in cancer has been hampered by its narrow therapeutic window. The main advance of SP-002 is a wide-therapeutic window where transduced tumors release local sustained IFN-γ allowing for a therapeutically effective dose to be delivered without causing significant systemic toxicities. Interferon-γ is a central orchestrator of an immune response (both adaptive and innate response), can induce programmed cell death in tumors, and restricts neo-vasculature supporting tumor growth.

Clinical Rationale

It is being developed as an effective, durable non-surgical intra-lesional treatment for treating multiple Basal Cell Carcinomas in Basal Cell Nevus Syndrome patients.

SP-002 with a Hedgehog Pathway Inhibitor (HHPI)

The combination regimen is being developed as an effective treatment for Locally Advanced Basal Cell Carcinoma. Basal cell carcinoma is a common skin cancer, with 3-4 million cases arising annually in the US. About 2% of these patients progress to advanced disease (about ~60,000 per yr. in the US). LA BCC comprise unresectable lesions, recurrent (multiple recurrences) lesions and lesions on anatomically difficult surgical sites that would result in significant functional damage upon resection.

Clinical Rationale

The HHPI (Hedgehog pathway inhibitors, e.g., vismodegib and sonidegib) are FDA-approved agents for use in LA BCC when surgery and radiotherapy are not suitable. Of the estimated that of 60,000 LA BCC patients, only a small subset use HHPIs. The primary reason for HHPI’s low adoption rate is the low Complete Response (CR) rate observed. HHPIs are effective at shrinking the majority of LA BCC but a quiescent population of residual BCC persist even while ongoing treament. Combining, SP-002 with an HHPI can improve clinical outcomes via complementary and synergistic mechanisms of action. SP-002, as an add-on to standard of care (SOC) HHPI, vismodegib, is anticipated to improve both CR rate and durability of response.

Rationale for add-on of SP-002 to HHPIs

HHPI Monotherapy – major ‘debulking’ of large BCCs

BCCs are heterogeneous with respects to HHPI responsiveness

BCCs are heterogeneous with respects to HHPI responsiveness 1-3

HHPI highly effective in majority of BCCs

HHPI highly effective in majority of BCCs 1-3

HHPI resistant residual BCC can lead to relapse ~CR~20-30%

HHPI resistant residual BCC can lead to relapse ~CR~20-30% 5

Quiescent residual BCCs express LGR5 cancer stem cell marker 1-3

HHPI & SP-002 Combination Therapy – ‘debulking’ and removal of HHPI resistant residual populations

BCCs are heterogeneous with respects to HHPI responsiveness

HHPI highly effective in majority of BCCs


HHPI plus SP-002

HHPI plus SP-002

Interferon – γ ablating residual BCCs (Interferon – γ reported to induce cell death in LGR5 stem cells) 4

Complete Responses Targeting CR >40-50%

1 Eberl et al, Cell 2018 33, 229

2 Biels et al, Nature 2018 562:429

3 Sánchez-Danés, Nature 2018 562:434

4 Takashima, et al Sci Immunol 2019 4:42

5 vismodegib product information sheet


SP-105 comprises SP-002 in combination with a controlled-release cox-2 inhibitor to enable the local release profile that can provide a wider therapeutic window.

Scientific Rationale

Cox-2 and PGE2 expression is induced as a broad response to multiple treatment modalities, such as chemotherapy, 1,2 radiotherapy,3–5 immunotherapy,6–11 and viral infections. Cox-2/PGE-2 expression can decrease the efficacy of these modalities leading to treatment resistance through the inactivation of programmed cell death pathways 12,13 and immunosuppression. 6,7,14–17 Cox-2/PGE2 expression is also a key constituent of wound healing 18,19 and regeneration that can then foster persistence, relapse, and recurrence of cancers.20–23 The initial impact of Cox-2/PGE2 can result in dampening of the immune inflammatory response, but subsequent activation of the regeneration program can result in the expansion and mobilisation of stem cells (and cancer stem cells) resulting in the replenishment of the tumor with treatment resistant cancer cells. 11,20,21,24–26

Cox-2 Inhibitors and SP-002 both promote adaptive immune responses and direct anti-tumor effects through complementary pathways. 26,27 A key part of the regulatory feedback that dampens the cellular inflammatory response driven by Interferon-γ signalling, is the induction of Cox-2 expression 28 which suppresses cellular immunity. 26,29 Cyclooxygenase-2 expression within the tumour stroma enhances PDL1 expression in tumour-associated macrophages and myeloid-derived suppressor cells (the PD1/PDL1 nexus is a major regulatory checkpoint that can shut-down T cell responses elicited by Interferon-γ signalling).29 A second major negative regulator of T cell responses elicited by Interferon-γ signalling are regulatory T cells (Tregs). Cox-2 expression has been shown to be potent inducers of regulatory T cells. 17


Preclinical IND enabling studies.

SP-500 Platform

The SP-500 oncolytic platform has been designed to address the intratumoral heterogeneity present in cancers that can often undermine durable responses.

Scientific Rationale

In multiple cancer settings, early treatment success evidenced by complete responses , can rapidly giveaway to resistant recurrent cancer. 30–34

This, in part, may be attributed to the heterogenous nature of tumours, often comprising subsets of varying susceptibility to therapeutic intervention and cell death. 32,33,35,36 Often, more stem-like/progenitor subsets, which may comprise only a minor fraction have a higher threshold for cell death and retain potent proliferative capacity. 37–40 While, more differentiated populations, that may comprise the bulk of the tumor, can have a lower cell death threshold, resulting in impressive early regressions and clinical responses. The more resistant residual populations can persist, undergo further genetic or epigenetic alteration, and drive resistant recurrences and remodel the tumor microenvironment for progression.

The SP-500 oncolytic platform has been designed to induce programmed cell death across intratumorally heterogeneous tumor by invoking multiple non-redundant effector pathways that can impart varying thresholds for cell death. These vectors also carry payloads that remodel the tumor microenvironment for tumor eradication and aid in efficient viral vector dispersion throughout the tumor microenvironment.


Lead optimization.


  1. Bell CR, Pelly VS, Moeini A, Chiang SC, Flanagan E, Bromley CP, et al. Chemotherapy-induced COX-2 upregulation by cancer cells defines their inflammatory properties and limits the efficacy of chemoimmunotherapy combinations. Nat Commun. 2022;13(1):2063. doi:10.1038/s41467-022-29606-9
  2. Nikolos F, Hayashi K, Hoi XP, Alonzo ME, Mo Q, Kasabyan A, et al. Cell death-induced immunogenicity enhances chemoimmunotherapeutic response by converting immune-excluded into T-cell inflamed bladder tumors. Nat Commun. 2022;13(1):1487. doi:10.1038/s41467-022-29026-9
  3. Chai Y, Calaf GM, Zhou H, Ghandhi SA, Elliston CD, Wen G, et al. Radiation induced COX-2 expression and mutagenesis at non-targeted lung tissues of gpt delta transgenic mice. Br J Cancer. 2013;108(1):91-98. doi:10.1038/bjc.2012.498
  4. Brocard E, Oizel K, Lalier L, Pecqueur C, Paris F, Vallette FM, et al. Radiation-induced PGE2 sustains human glioma cell growth and survival through EGF signaling. Oncotarget. 2015;6(9):6840-6849. doi:10.18632/oncotarget.3160
  5. Davis TW, O’Neal JM, Pagel MD, Zweifel BS, Mehta PP, Heuvelman DM, et al. Synergy between Celecoxib and Radiotherapy Results from Inhibition of Cyclooxygenase-2-Derived Prostaglandin E2, a Survival Factor for Tumor and Associated Vasculature. Cancer Res. 2004;64(1):279-285. doi:10.1158/0008-5472.can-03-1168
  6. Pu D, Yin L, Huang L, Qin C, Zhou Y, Wu Q, et al. Cyclooxygenase-2 Inhibitor: A Potential Combination Strategy With Immunotherapy in Cancer. Front Oncol. 2021;11:637504. doi:10.3389/fonc.2021.637504
  7. Boumelha J, Castro A de, Bah N, Cha H, Trécesson S de C, Rana S, et al. CRISPR/Cas9 screen identifies KRAS-induced COX-2 as a driver of immunotherapy resistance in lung cancer. bioRxiv. Published online 2023:2023.04.13.536740. doi:10.1101/2023.04.13.536740
  8. Li Y, Fang M, Zhang J, Wang J, Song Y, Shi J, et al. Hydrogel dual delivered celecoxib and anti-PD-1 synergistically improve antitumor immunity. Oncoimmunology. 2015;5(2):e1074374. doi:10.1080/2162402x.2015.1074374
  9. Lemos H, Ou R, McCardle C, Lin Y, Calver J, Minett J, et al. Overcoming resistance to STING agonist therapy to incite durable protective antitumor immunity. J Immunother Cancer. 2020;8(2):e001182. doi:10.1136/jitc-2020-001182
  10. Li Y, Fang M, Zhang J, Wang J, Song Y, Shi J, et al. Hydrogel dual delivered celecoxib and anti-PD-1 synergistically improve antitumor immunity. OncoImmunology. 2016;5(2):e1074374. doi:10.1080/2162402x.2015.1074374
  11. Pi C, Jing P, Li B, Feng Y, Xu L, Xie K, et al. Reversing PD-1 Resistance in B16F10 Cells and Recovering Tumour Immunity Using a COX2 Inhibitor. Cancers. 2022;14(17):4134. doi:10.3390/cancers14174134
  12. Winfield LL, Payton-Stewart F. Celecoxib and Bcl-2: emerging possibilities for anticancer drug design. Futur Med Chem. 2012;4(3):361-383. doi:10.4155/fmc.11.177
  13. SHAO D, KAN M, QIAO P, PAN Y, WANG Z, XIAO X, et al. Celecoxib induces apoptosis via a mitochondria-dependent pathway in the H22 mouse hepatoma cell line. Mol Med Rep. 2014;10(4):2093-2098. doi:10.3892/mmr.2014.2461
  14. Yan G, Zhao H, Zhang Q, Zhou Y, Wu L, Lei J, et al. A RIPK3-PGE2 circuit mediates myeloid-derived suppressor cell-potentiated colorectal carcinogenesis. Cancer Res. 2018;78(19):canres.3962.2017. doi:10.1158/0008-5472.can-17-3962
  15. Tudor DV, Bâldea I, Lupu M, Kacso T, Kutasi E, Hopârtean A, et al. COX-2 as a potential biomarker and therapeutic target in melanoma. Cancer Biol Med. 2020;17(1):20-31. doi:10.20892/j.issn.2095-3941.2019.0339
  16. Rodríguez-Ubreva J, Català-Moll F, Obermajer N, Álvarez-Errico D, Ramirez RN, Company C, et al. Prostaglandin E2 Leads to the Acquisition of DNMT3A-Dependent Tolerogenic Functions in Human Myeloid-Derived Suppressor Cells. Cell Rep. 2017;21(1):154-167. doi:10.1016/j.celrep.2017.09.018
  17. Sharma S, Yang SC, Zhu L, Reckamp K, Gardner B, Baratelli F, et al. Tumor Cyclooxygenase-2/Prostaglandin E2–Dependent Promotion of FOXP3 Expression and CD4+CD25+ T Regulatory Cell Activities in Lung Cancer. Cancer Res. 2005;65(12):5211-5220. doi:10.1158/0008-5472.can-05-0141
  18. Futagami A, Ishizaki M, Fukuda Y, Kawana S, Yamanaka N. Wound Healing Involves Induction of Cyclooxygenase-2 Expression in Rat Skin. Lab Investig. 2002;82(11):1503-1513. doi:10.1097/01.lab.0000035024.75914.39
  19. Futagami A, Ishizaki M, Fukuda Y, Kawana S, Yamanaka N. Wound Healing Involves Induction of Cyclooxygenase-2 Expression in Rat Skin. Lab Investig. 2002;82(11):1503-1513. doi:10.1097/01.lab.0000035024.75914.39
  20. Kurtova AV, Xiao J, Mo Q, Pazhanisamy S, Krasnow R, Lerner SP, et al. Blocking PGE2-induced tumour repopulation abrogates bladder cancer chemoresistance. Nature. 2015;517(7533):209-213. doi:10.1038/nature14034
  21. Pang LY, Hurst EA, Argyle DJ. Cyclooxygenase-2: A Role in Cancer Stem Cell Survival and Repopulation of Cancer Cells during Therapy. Stem Cells Int. 2016;2016:2048731. doi:10.1155/2016/2048731
  22. Kawaue T, Yow I, Le AP, Lou Y, Loberas M, Shagirov M, et al. Mechanics defines the spatial pattern of compensatory proliferation. bioRxiv. Published online 2021:2021.07.04.451019. doi:10.1101/2021.07.04.451019
  23. Sobolewski C, Cerella C, Dicato M, Ghibelli L, Diederich M. The Role of Cyclooxygenase-2 in Cell Proliferation and Cell Death in Human Malignancies. Int J Cell Biol. 2010;2010:215158. doi:10.1155/2010/215158
  24. Jiang GB, Fang HY, Tao DY, Chen XP, Cao FL. COX-2 potentiates cisplatin resistance of non-small cell lung cancer cells by promoting EMT in an AKT signaling pathway-dependent manner. Eur Rev Méd Pharmacol Sci. 2019;23(9):3838-3846. doi:10.26355/eurrev_201905_17811
  25. Botti G, Fratangelo F, Cerrone M, Liguori G, Cantile M, Anniciello AM, et al. COX-2 expression positively correlates with PD-L1 expression in human melanoma cells. J Transl Med. 2017;15(1):46. doi:10.1186/s12967-017-1150-7
  26. Zuo C, Qiu X, Liu N, Yang D, Xia M, Liu J, et al. Interferon-α and cyclooxygenase-2 inhibitor cooperatively mediates TRAIL-induced apoptosis in hepatocellular carcinoma. Exp Cell Res. 2015;333(2):316-326. doi:10.1016/j.yexcr.2015.02.013
  27. Nakanishi Y, Nakatsuji M, Seno H, Ishizu S, Akitake-Kawano R, Kanda K, et al. COX-2 inhibition alters the phenotype of tumor-associated macrophages from M2 to M1 in Apc Min/+ mouse polyps. Carcinogenesis. 2011;32(9):1333-1339. doi:10.1093/carcin/bgr128
  28. Matsuura H, Sakaue M, Subbaramaiah K, Kamitani H, Eling TE, Dannenberg AJ, et al. Regulation of Cyclooxygenase-2 by Interferon γ and Transforming Growth Factor α in Normal Human Epidermal Keratinocytes and Squamous Carcinoma Cells ROLE OF MITOGEN-ACTIVATED PROTEIN KINASES*. J Biol Chem. 1999;274(41):29138-29148. doi:10.1074/jbc.274.41.29138
  29. Göbel C, Breitenbuecher F, Kalkavan H, Hähnel PS, Kasper S, Hoffarth S, et al. Functional expression cloning identifies COX-2 as a suppressor of antigen-specific cancer immunity. Cell Death Dis. 2014;5(12):e1568-e1568. doi:10.1038/cddis.2014.531
  30. Rossi A, Roberto M, Panebianco M, Botticelli A, Mazzuca F, Marchetti P. Drug resistance of BRAF-mutant melanoma: Review of up-to-date mechanisms of action and promising targeted agents. Eur J Pharmacol. 2019;862:172621. doi:10.1016/j.ejphar.2019.172621
  31. Prihantono, Faruk M. Breast cancer resistance to chemotherapy: When should we suspect it and how can we prevent it? Ann Med Surg. 2021;70:102793. doi:10.1016/j.amsu.2021.102793
  32. Sánchez-Danés A, Larsimont JC, Liagre M, Muñoz-Couselo E, Lapouge G, Brisebarre A, et al. A slow-cycling LGR5 tumour population mediates basal cell carcinoma relapse after therapy. Nature. 2018;562(7727):434-438. doi:10.1038/s41586-018-0603-3
  33. Biehs B, Dijkgraaf GJP, Piskol R, Alicke B, Boumahdi S, Peale F, et al. A cell identity switch allows residual BCC to survive Hedgehog pathway inhibition. Nature. 2018;562(7727):429-433. doi:10.1038/s41586-018-0596-y
  34. Penter L, Liu Y, Wolff JO, Yang L, Taing L, Jhaveri A, et al. Mechanisms of response and resistance to combined decitabine and ipilimumab for advanced myeloid disease. Blood. 2023;141(15):1817-1830. doi:10.1182/blood.2022018246
  35. Eberl M, Mangelberger D, Swanson JB, Verhaegen ME, Harms PW, Frohm ML, et al. Tumor Architecture and Notch Signaling Modulate Drug Response in Basal Cell Carcinoma. Cancer Cell. 2018;33(2):229-243.e4. doi:10.1016/j.ccell.2017.12.015
  36. Calzolari D, Paternostro G, Harrington PL, Piermarocchi C, Duxbury PM. Selective Control of the Apoptosis Signaling Network in Heterogeneous Cell Populations. PLoS ONE. 2007;2(6):e547. doi:10.1371/journal.pone.0000547
  37. Wong CC, Kang W, Xu J, Qian Y, Luk STY, Chen H, et al. Prostaglandin E2 induces DNA hypermethylation in gastric cancer in vitro and in vivo. Theranostics. 2019;9(21):6256-6268. doi:10.7150/thno.35766
  38. Magee JA, Piskounova E, Morrison SJ. Cancer Stem Cells: Impact, Heterogeneity, and Uncertainty. Cancer Cell. 2012;21(3):283-296. doi:10.1016/j.ccr.2012.03.003
  39. [39] Melzer C, Ohe J von der, Lehnert H, Ungefroren H, Hass R. Cancer stem cell niche models and contribution by mesenchymal stroma/stem cells. Mol Cancer. 2017;16(1):28. doi:10.1186/s12943-017-0595-x
  40. Angelis D, Francescangeli, Zeuner. Breast Cancer Stem Cells as Drivers of Tumor Chemoresistance, Dormancy and Relapse: New Challenges and Therapeutic Opportunities. Cancers. 2019;11(10):1569. doi:10.3390/cancers11101569