UNITED STATES
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FORM
CURRENT REPORT
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| Item 8.01 | Other Events |
On September 30, 2022, the previously announced proffered talk titled “Objective clinical response by KRAS mutation-specific TCR-T cell therapy in previously treated advanced Non-small cell lung cancer,” was given at the CRI-ENCI-AACR Sixth International Cancer Immunotherapy Conference. A copy of the presentation is filed as Exhibit 99.1 to this Current Report on Form 8-K and is incorporated herein by reference.
| Item 9.01 | Financial Statements and Exhibits. |
(d) Exhibits.
| Exhibit No. |
Description | |
| 99.1 | Presentation. | |
| 104 | Cover Page Interactive Data File (embedded within the Inline XBRL document). | |
SIGNATURES
Pursuant to the requirements of the Securities Exchange Act of 1934, the registrant has duly caused this report to be signed on its behalf by the undersigned hereunto duly authorized.
| Alaunos Therapeutics, Inc. | ||||||
| Date. September 30, 2022 | By: | /s/ Melinda Lackey | ||||
| Name: | Melinda Lackey | |||||
| Title: | Senior Vice President, Legal | |||||
Exhibit 99.1 Objective clinical response by KRAS mutation- specific TCR-T cell therapy in previously treated advanced non-small cell lung cancer Marcelo V. Negrao, MD Assistant Professor Department of Thoracic / Head and Neck Medical Oncology University of Texas MD Anderson Cancer Center
Forward Looking Statements Disclaimer This presentation contains forward-looking statements as defined in the Private Securities Litigation Reform Act of 1995, as amended. Forward-looking statements are statements that are not historical facts, and in some cases can be identified by terms such as “may,” “will,” “could,” “expects,” “plans,” “anticipates,” “believes” or other words or terms of similar meaning. These statements include, but are not limited to, statements regarding Alaunos Therapeutics, Inc.'s ( Alaunos or the Company ) business and strategic plans, the anticipated outcome of preclinical and clinical studies by the Company or its third-party collaborators, the Company’s manufacturing capabilities and the timing of the Company's research and development programs. Although the management team of Alaunos believes that the expectations reflected in such forward-looking statements are reasonable, investors are cautioned that forward-looking information and statements are subject to various risks and uncertainties, many of which are difficult to predict and generally beyond the control of Alaunos, that could cause actual results and developments to differ materially from those expressed in, or implied or projected by, the forward-looking information and statements. These risks and uncertainties include, among other things, the uncertainties inherent in research and development, future clinical data and analysis, whether any of Alaunos’ product candidates will advance further in the preclinical research or clinical trial process, including receiving clearance from the U.S. Food and Drug Administration or equivalent foreign regulatory agencies to conduct clinical trials and whether and when, if at all, they will receive final approval from the U.S. Food and Drug Administration or equivalent foreign regulatory agencies and for which indication and risk factors discussed or identified inthe public filings with the Securities and Exchange Commission made by Alaunos, including those risks and uncertainties listed inthe most recent periodic report filed by Alaunos with the Securities and Exchange Commission. This information is being provided as of the date of this presentation, and Alaunos does not undertake any obligation to update or revise the information containedin this presentation whether as a result of new information, future events, or any other reason.
Adoptive T-Cell Therapy has Activity in Solid Tumors 1 ▪ Melanoma: expanded TILs ORR 34-56% 2 ▪ HPV+ SCC: HPV-TIL ORR 18-28% 3 ▪ MBC: enriched TILs ORR 67% 4 ▪ NSCLC: expanded TILs response rate 46% 5 ▪ CRC: TIL produced durable response 6 ▪ PDAC: durable response and persistence of TCR-T cells 1. Rosenberg et al. Science 2015 / 2. Stevanonic et al. CCR 2019 / 3. Zacharakis et al. JCO 2022 / 4. Creelan et. al Nature Medicine 2021 / 5. Tran et al. NEJM 2016 / 6. Leidner et al. NEJM 2022
KR AS Mutations are Logical Targets for T-Cell Therapy due to High Prevalence in Epithelial Solid Tumors Lung CholangioCA Adenocarcinoma Key: G12C Pancreatic G12D Ovarian Adenocarcinoma G12V Other KRAS Mut. Wild Type KRAS Colorectal Endometrial Adenocarcinoma 1 Judd et al. Mol Cancer Ther. 2021 2 Catalogue of Somatic Mutations in Cancer (COSMIC) database https://cancer.sanger.ac.uk/cosmic
Phase I/II Trial to Determine the Safety and Efficacy of Non-viral TCR-T Cell Therapy for Treatment of Solid Tumors ▪ ClinicalTrials.gov: NCT05194735 ▪ Solid tumors failed 1+ lines of therapy ▪ HLA + cancer gene mutation match for TCR library ▪ Accelerated dose escalation: BOIN design 9 9 9 ▪ 3 dose levels: 1 - <10x10 / 10 - <70x10 / 70 - 150x10 ▪ Objectives: safety / RP2D / manufacturing feasibility Manufacturing Treatment/Follow-Up Long-Term Follow-Up 13 YEARS D -30 D -7 D 0 D 42 D 84 Y2 or (FDA Requirement) Manufacturing Lymphodep. Product Imaging (every 3 months) progression Start Start Infusion Imaging Negrao et al. ASCO 2022 / Morelli et al. ESMO 2022
TCR Library Designed to Target Tumor Neoantigens Derived from Hotspot Mutations ▪ Common cancer gene mutations: KRAS, TP53, EGFR ▪ Common HLAs: A*02:01 / A*11:01 ▪ Library expansion: identification of novel anti-tumor reactive TCRs ▪ More TCRs = more eligible patients Genes Mutations HLA Types G12D A*11:01 / C*08:02 KRAS G12V A*11:01 / C*01:02 R175H A*02:01 / DRB1*13:01 TP53 R248W A*68:01 Y220C A*02:01 / DRB3*02:02 EGFR E746-A750del DPB1*01:01
Non-viral Sleeping Beauty System Designed to Enable Manufacture of TCR-T Cells without Complex Gene Editing ▪ Efficient integration without the complexity of gene editing or viral approaches ▪ Rapid, cost-effective manufacturing ▪ Accommodates large transgene size ▪ Expected to be scalable for clinical production
Patient 1: Immune Checkpoint Inhibitor and Chemotherapy Refractory KRAS G12D NSCLC ▪ 34yo, female, never smoker, lung adenocarcinoma ▪ Left lower lobectomy and adjuvant cisplatin and vinorelbine x 4 cycles ▪ Disease recurrence in the lungs 4 months after adjuvant treatment ▪ KRAS G12D mutation positive / tumor PD-L1 expression = 10% ▪ Carboplatin, pemetrexed, pembrolizumab x 4 cycles with response followed by pemetrexed and pembrolizumab maintenance x 22 cycles with disease progression
Patient 1: Immune Checkpoint Inhibitor and Chemotherapy Refractory KRAS G12D NSCLC ▪ Durvalumab + CTLA4 inhibitor + MEK inhibitor on trial – discontinued due to progression ▪ SHP2 inhibitor single-agent on trial – discontinued due to progression ▪ Library TCR match: KRAS G12D HLA-A*11:01
TCR-T Cells Observed to Specifically Recognize and Kill Targets Expressing KRAS G12D Presented by HLA-A*11:01 Neoantigen-Specific Activation Effector Cytokine Secretion Tumor Killing ✱✱✱ 100 100 80 80 60 60 Mutant KRAS G12D Mutant KRAS G12D 40 40 Wild Type KRAS 20 20 Wild Type KRAS 0 0 [peptide], μg/mL IFN-γ pg/mL Preclinical Data 0 3 5×10 4 1×10 4 1.5×10 4 2×10 4 2.5×10 Wild Type KRAS Mutant KRAS G12D % mTCR+41BB+ (CD8+ T cells) 0.0001 DMSO 0.001 0.01 0.1 1 10 Specific Lysis (%)
High TCR Expression and Purity of TCR-T Cells Manufactured with Sleeping Beauty Transposition TCR-T Infusion Product (Patient 1: KRAS G12D/HLA-A*11:01) Result Viability 95.1% 9 Total TCR-T Cells 9x10 CD3+ Purity 99.7% TCR+ 95.2% CD4:CD8 Ratio 0.32 VCN 5
Patient 1 Had Manageable Safety Events During Lymphodepletion Chemotherapy Chest Pain - Small R pneumothorax Related to pre-treatment biopsy Hospital Admission Lymphodepletion Days of Administration Dose Drug (LD) Prior to TCR-T Infusion Cyclophosphasmide 60 mg/kg -8, -7 2 Fludarabine 25 mg/m -8, -7, -5, -4, -3 Day -9 -8 -7 -6 -5 -4 -3 Note: Day -6 Fludarabine dose withheld Hypoxia Gr2 / Hypotension Gr3 / Tachycardia Gr3 O2 nasal cannula 3L / hydration w/ albumin Related to LD chemotherapy LD = Lymphodepletion
Patient 1 Had Manageable Safety Events After Lymphodepletion Chemotherapy and TCR-T cell infusion CRS Gr2 – 6hrs post-TCR-T infusion Hypoxia / Tachycardia / Fever O2 nasal cannula 2L / anti-pyretics / IV fluids / self-limited Hospital Discharge TCR-T Cell Day 11 Infusion TCR-T Cell Target Dose 9 9x10 TCR+ T Cells KRAS G12D/HLA-A*11:01 Day -2 -1 0 1 2 3 4 5 6 7 14 (Dose Level 1) Anemia – Hb 7.0 – Gr3 PRBC 1 unit - D5 Thrombocytopenia – 22k – Gr4 Self-limited / no bleeding
Patient 1 Had Transient Elevation in Inflammatory Cytokines Associated with Onset and Resolution of CRS CRS = Cytokine Release Syndrome
Patient 1: Complete Resolution of Right Lower Lobe Lesion Insert Image Here Insert Image Here Insert Image Here 0 6 12 Baseline Week 6 Week 12 1.3 cm 0.0 cm 0.0 cm
Patient 1: Reduction of Right Upper Lobe Lesion 0 6 12 Baseline Week 6 Week 12 1.3 cm 1.1 cm 1.0 cm
Patient 1: Reduction of Right Hilar Lymphadenopathy and of Non-Measurable Right Upper Lobe Lesion 0 6 12 Baseline Week 6 Week 12 1.5 cm 1.1 cm 1.0 cm
Patient 1 Had a Confirmed Objective Partial Response at Week 12 Baseline Week 6 Week 12 Target Lesions (mm) #1: Right lower lobe 13 0 0 #2: Right upper lobe 13 11 10 #3: Right hilar lymph node 15 11 10 Sum of Diameters (mm) 41 22 20 Percent Change -46.30% -51.20% Non-Target Lesions Bilateral lung nodules Non-CR/Non-PD Non-CR/Non-PD Overall Response Partial Response Partial Response
Patient 1 TCR-T Cells Exhibited Rapid Expansion and Ongoing Persistence at Week 12 Circulating TCR-T Cells Day 4 Week 12 1250 1000 TCR-T Cells/uL 1,038 134 5 4 750 TCR-T Copies/μg 5x10 2.5x10 500 % TCR-T+ of CD3+ 98.4% 22.5% 250 0 0 2 4 6 8 12 Weeks Post-Infusion Baseline Day 4 Week 4 Week 6 Week 12 CD3 0.6% 98.4% 42.0% 10.0% 22.5% Gated on CD3+ TCR-T (of CD3+) TCR-T Cells / μL Blood
TCR-T Cells / μL Blood Patient 1 Serum Interferon-γ was Associated with TCR-T Cell Expansion and Persistence 750 1250 TCR-T Cells CRS IFN-γ 600 1000 450 750 300 500 150 250 0 0 0 1 2 4 6 8 10 12 Weeks Post-Infusion CRS = Cytokine Release Syndrome IFN-γ Serum Conc. [pg/mL]
Patient 2: Previously Treated Advanced CRC ▪ 54yo, female, metastatic colorectal cancer ▪ Progressed on one prior line of therapy (FOLFIRI+Bevacizumab) ▪ Library TCR match: TP53 R175H HLA-A*02:01 9 ▪ TCR-T infusion of 64x10 TCR-T cells - Dose Level 2
Patient 2 Had Manageable Safety Events After TCR-T Cell Infusion CRS Gr3 Fever / Hypotension / Tachycardia / Hypoxia O2 HFNC 40L 50% and Tocilizumab TCR-T Cell Target Dose TCR-T Cell 9 Hospital 64x10 TCR+ T Cells TP53 R175H/HLA-A*02:01 Infusion Admission (Dose Level 2) Lymphodepletion Days of Administration Hospital Dose -8 -6 -4 -2 0 2 4 DAY Drug Prior to TCR-T Infusion Discharge Cyclophosphasmide 60 mg/kg -7, -6 Day 13 CRS Gr2 2 Fludarabine 25 mg/m -7, -6, -5, -4, -3 Hypoxia O2 Nasal Cannula 4L HFNC = High flow nasal cannula
Patient 2 Achieved Best Overall Response of Stable Disease Baseline Week 6 Week 12 Target Lesions #1: Pelvic Mass (mm) 65 48 67 #2: Retroperitoneal Lymph Node (mm) 27 30 28 Sum of Diameters (mm) 92 78 95 Percent Change -15.20% 21.80% New Lesion No Liver / Lung Stable Progressive Overall Response Disease Disease Note: Patient off study due to disease progression
Treatment of Patients 1 and 2 was Tolerable with a Manageable Safety Profile ▪ Cytopenias expected with lymphodepletion regimen were observed in both patients ▪ Manageable CRS observed • No mechanical ventilation • No ICU admission • No vasopressors ▪ No TCR-T cell related DLTs ▪ No ICANS DLT = Dose limiting toxicity; ICANS = Immune effector cell-associated neurotoxicity syndrome
Confirmed Objective Response in Immune Checkpoint Inhibitor Refractory KRAS G12D-mutant NSCLC Treated with TCR-T Cells ▪ Immune checkpoint inhibitor refractory advanced NSCLC patient treated with TCR-T cells has confirmed partial response ▪ First confirmed response to TCR-T cell therapy targeting hotspot cancer gene mutation in advanced NSCLC to our knowledge ▪ KRAS G12D / HLA-A*11:01: viable target for TCR-T cell therapy
S leeping Beauty System is a Promising Platform for TCR-T Cell Therapy and Trial Enrollment is Ongoing ▪ First report of successful TCR-T cell therapy using non-viral Sleeping Beauty system for solid tumors ▪ Proof of concept of manufacturing TCR-T targeting KRAS and TP53 ▪ Ongoing persistence of TCR-T cells at Week 12 at Dose Level 1 in Patient 1 ▪ Phase I dose escalation: enrollment ongoing for patients with advanced solid tumors harboring KRAS, TP53 and EGFR mutations
Acknowledgements MDACC Study Team Alaunos Therapeutics Marcelo V. Negrao Nathan Demars Maria Pia Morelli Jaymes Holland Partow Kebriaei Matthew R. Collinson-Pautz Amir Jazaeri Frances Adeyemi Benny Johnson Amanda Montoya Thank you to all Shubham Pant Victor Carpio the patients and Laura Henderson Lauren Heese Lauren McGuire Jourdan Anderson their families Rasoul Irannezhad Victor Cruz Veronica Novegil Vanessa Jackson Kamisha Jernigan Kim Cooper John V. Heymach Beatriz A. Santillan Scott E. Kopetz Abhishek Srivastava Ron Weitzman ClinicalTrials.gov: NCT05194735 Drew Deniger