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ALETA CNS metastasis program 8 July 2020
The document discusses advancements in CAR T-cell therapies, particularly the development of a novel technology aimed at improving the effectiveness of these treatments for solid tumors, including innovative bridging proteins that enhance T-cell targeting. It emphasizes the specific success of anti-CD19 CAR T-cells in providing durable responses in patients while addressing significant challenges such as persistence, fitness, and antigen escape. The text concludes with a focus on the clinical potential of these therapies for treating CNS metastases in her2-positive cancer patients.
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ALETA CNS metastasis program 8 July 2020
- 1. A Novel Platformfor Cell Therapeutics Our Journey from Bench to Clinical Development 8 July 2020 Paul D Rennert, President & CSO, Aleta Biotherapeutics
- 2. CAR T cellswork because they bind tumor antigens Cytotoxicity: This encounter triggers the CAR T cell to secrete factors that kill the tumor cells Serial killing: Each CAR T cell can find and kill up to 1000 tumor cells Proliferation: During that time the CAR T cell reproduces again and again, creating clones of itself that can carry on the anti-tumor activity Persistence: The target tumor protein must be consistently expressed at a high enough level to support CAR T cell expansion and persistence in the patient OCTS July 7-9, 20202
- 3. When they work,cell therapies produce amazing and curative benefit in relapsed patients with no other recourse Approved anti-CD19 CAR T cell therapies for refractory B cell leukemia and lymphomas Emily Whitehead, 8 years after treatment with Kymriah, with no trace of leukemia, and still carrying her CAR T cells OCTS July 7-9, 20203
- 4. OCTS July 7-9,20204 CAR-T cells that target CD19 have exemplary characteristics • CAR-T cell persistence is a natural attribute of anti-CD19 CAR T cells because they can expand and persist using normal CD19+ B cells ‣ Normal B cells are a non-tumor dependent, self-renewing antigen source ‣ This antigen depot allows the CAR T cells to outlast and outlive the tumor cells • CAR-T cell fitness is naturally enhanced by the interaction with normal B cells • anti-CD19 CAR T cells are known to traffic throughout the patient, including into the central nervous system Persistence, fitness, trafficking
- 5. Other CAR Tcells just don’t work as well: why not? OCTS July 7-9, 20205
- 6. Critical issues confrontCAR T cell therapeutics for solid tumors • CAR T Cell Persistence is often poor in solid tumor indications • CAR T Cell Fitness can be limited by exhaustion and immunosuppression • CAR T Cell Trafficking may limit access to the tumor • Antigen Escape thwarts therapy due to the loss of tumor antigen expression • Patient Safety can be compromised when CAR T cells attack critical normal cells and tissues 6 OCTS July 7-9, 2020
- 7. Our technology hastwo key elements designed to tackle these critical issues OCTS July 7-9, 20207 • The CAR T cell that has exemplary properties, eg. an anti-CD19 CAR T cell • Bridging Protein technology - CAR-T Engagers link CAR T cells to whatever antigen(s) we wish to target
- 8. Bridging proteins asanti- CD19 CAR T Engagers OCTS July 7-9, 2020 8 an anti-tumor antigen domain (eg. with an scFv) with two anti-tumor antigen domains (eg. with two different llama VH) with an anti-tumor antigen VH and an anti-albumin VH • single antigen • dual antigen • half-life extended PromoterCAR192Adualepitopebridgingprotein CAR19 omoterCAR192Adualepitopebridgingprotein CAR19 CD19 VH-1 VH-2 CAR19 CD19 PromoterCAR192Adualepitopebridgingprotein CAR19CD19 CAR19 2A dual epitope bridging protein VH-1 VH-2 Vh Vl
- 9. Delivery of bridgingproteins OCTS July 7-9, 2020 9 • Biologic delivery by injection • Lentiviral delivery from a CAR T cell • Oncolytic viral delivery from a targeted tumor cell
- 10. Bridging protein characteristics: -simple, modular, multi-antigen, adaptable OCTS July 7-9, 2020 10 Anti-CD19 CAR T cell characteristics: - persistence, fitness, trafficking
- 11. Putting the piecestogether … OCTS July 7-9, 2020 11
- 12. Bridging proteins coatany tumor cell with CD19 • The bridging protein is the CD19 extracellular domain linked to antibody domains that bind to tumor antigens, thus coating the tumor with CD19. the antibody fragment binds a tumor antigen 12 OCTS July 7-9, 2020 PromoterCAR192Adualepitopebridgingprotein CAR19CD19 CAR19 Tumor Celltumor antigen binding CD19 CAR19 PromoterCAR192Adualepitopebridgingprotein CAR19CD19 target antigens Any tumor cell can be coated with CD19
- 13. Bridging proteins directanti-CD19 CAR T cells to attack any tumor cell anti-tumor protein 13 OCTS July 7-9, 2020 PromoterCAR192Adualepitopebridgingprotein CAR19CD19 CAR19 Tumor Celltumor antigen binding CD19 CAR19 PromoterCAR192Adualepitopebridgingprotein CAR19CD19 anti-CD19 CAR T cell add CAR T cells tumor cells are killedCAR T cell sees CD19
- 14. Promoter CAR19 2Adual epitope bridging protein CAR19 CD19-anti-tumor antigen • How best to deliver the bridging protein so that it can get to the tumor? • Viral expression allows the CAR T cells to secrete the bridging protein, eg. lentiviral expression from a T cell: “all-in-one delivery” AR192Adualepitopebridgingprotein CD19 14 The bridging protein sequence is secreted by anti-CD19 CAR T cell The CAR is on the T cell surface The bridging protein is secreted from the T cell OCTS July 7-9, 2020
- 15. The bridging proteinsequence can be encoded into the CAR itself • Secreted bridging proteins (blue) coat a solid tumor cell (red) with CD19 • Now, any CAR-CD19 T cell that “sees” the CD19 will kill this solid tumor cell OCTS July 7-9, 202015 CAR-CD19 T cell CAR domain (anti-CD19) • Using a lentiviral vector, we engineer the CAR-CD19 T cell to secrete bridging proteins – this creates a Trojan Horse: the CAR T cell delivers its own CAR-T engager to attack the tumor
- 16. Aleta-002 Treatment of Breastand Lung Cancer Patients with Her2+ CNS Metastases Stage: IND Enablement OCTS July 7-9, 202016 Clinical translation example
- 17. The bridging proteinsequence can be encoded into the CAR itself CD19-anti-Her2 BP triggers potent cytotoxicity at sub- nM concentrations OCTS July 7-9, 202017 CAR-CD19 T cell CAR domain (anti-CD19) • Aleta-002 ---- CAR-CD19 T cells that secrete a CD19-anti-Her2 bridging protein PromoterCAR192Adualepitopebridgingprotein CAR19CD19 anti-Her2
- 18. OCTS July 7-9,2020 Her2-bridging CAR19 T cells secreting a bridging protein cure solid tumors in vivo • CAR-CD19 T cells that secrete a CD19-anti-Her2 scFv bridging protein were injected into mice carrying Her2-positive ovarian carcinoma cells 18 DIED --- treated with control CARs, or untreated CURED --- treated with CAR-CD19 T cells that secrete the CD19-anti-Her2 scFv bridging protein
- 19. These CARs stillrespond to CD19 – mice re-challenged with a CD19+ cell (Nalm6) 19 We took 4 of the survivors and re-challenged them, this time with CD19-positive Nalm6 cells; as a control we enrolled 3 naive mice: 0 5 10 15 20 0 5×107 1×108 1.5×108 2×108 2.5×108 ALT19-14 Nalm6 challenge days post Nalm6 Fluxtotal non-confidential disclosure cured mice naïve mice cured mice: no tumor growth naïve mice: lethal leukemia
- 20. non-confidential disclosure Re-stimulation ofHer2-bridging CAR-CD19 T cells 20 • Serial re-stimulation assays evaluate cytotoxicity and proliferation • Re-stimulation by a B cell line, but not a solid tumor cell line, profoundly induced robust CAR T cell proliferation • Remaining cells in each case are cytotoxic – the extent of proliferation is different • This remarkable result may further explain the poor expansion and persistence properties of CAR T cell directed to solid tumor antigens SKOV3 restimulation RAJI restimulation CAR-only CAR+SKOV3 CAR-only CAR+RAJI day 4, 1 stimulation day 8, 2 stimulations day 12, 3 stimulations day 15, 4 stimulations
- 21. This cell therapyis uniquely and specifically designed to treat Her2-positive CNS metastases – a huge clinical need • 270,000 newly diagnosed breast cancer patients/US/year, 20% are Her2-positive • 230,000 newly diagnosed lung cancer patients/US/year, ~5% are Her2-positive 230,000 newly diagnosed colorectal cancer patients/US/year, ~4% are Her2-positive Relapsing Her2-positive cancer patients commonly have CNS metastases Relapsing patients with CNS metastases have a poor prognosis and limited therapeutic options – antibody therapy does not treat CNS disease OCTS July 7-9, 202021
- 22. Using Her2-bridging CAR-CD19T cells to treat CNS metastases • The CAR T cells will expand in the periphery due to the provision of CD19+ normal B cells • Activated CAR T cells will productively traffic into the CNS ‣ CNS-resident B cell leukemias and lymphomas are cleared in patients successfully treated with CAR- CD19 cellular therapy • CAR T cells that exit the CNS will encounter B cells again in the periphery 22 OCTS July 7-9, 2020
- 23. • This isan indication where our technology provides a unique advantage – activation and persistence provided systemically (CD19-positive B cells) and locally - at the site of Her2- positive metastasis in the CNS. • Patients remain on standard of care therapy to control systemic disease = they do not have to stop trastuzumab/pertuzumab treatment. • These therapeutic profile is wholly unique and cannot be achieved by CARs directed to Her2 or by any biologic therapies. Aleta-002: Program value and differentiation OCTS July 7-9, 202023
- 24. Aleta-003 Treatment of CNSCancers with multi-antigen targeting CAR T therapy Stage: preclinical 24 OCTS July 7-9, 2020 Program extension
- 25. Examples Patients AntigensExpressed Glioblastoma / astrocytoma • pediatric and adult Her2, B7H3, IL13Ra2 Medulloblastoma • rare pediatric cancer • very rare in adults Her2, B7H3, B7H6 Ependymoma • rare pediatric cancer • very rare in adults Her2, B7H3, B7H6 Meningioma • pediatric and adult Her2, B7H3, IL13Ra2 Antigen selection for refractory CNS tumors • How can we create a therapeutic to treat diverse CNS cancers? • We focused on the pattern of tumor protein expression, and then designed bispecific bridging proteins that Her2, B7H3 and other tumor antigens 25
- 26. CAR-CD19-mediated cytotoxicity by singleand dual-antigen bridging proteins 26 single dual single IC50 = 100pM = 6 ngs/ml dual IC50 = 2.5 pM = 200 pgs/ml • single antigen and dual antigen targeting of a breast cancer cell line • dual antigen targeting shifts potency dramatically • antigen expression patterns suggest safe targeting combinations • local delivery is possible (eg. AdV)
- 27. OCTS July 7-9,2020 Aleta’s Pipeline: diverse programs moving into development 27 Dual-Antigen
- 28. Thank you OCTS July7-9, 2020