8-K
Century Therapeutics, Inc. (IPSC)
8-K
2021-12-16
For: 2021-12-16
View Original
Added on
April 11, 2026
UNITED STATES
SECURITIES AND EXCHANGE COMMISSION
Washington, DC 20549
FORM 8-K
CURRENT REPORT
Pursuant to Section 13 or 15(d)
of the Securities Exchange Act of 1934
Date of Report (Date of earliest event reported):December 16, 2021
Century Therapeutics, Inc.
(Exact name of registrant as specified in its charter)
| Delaware | 001-40498 | 84-2040295 |
|---|---|---|
| (State or other jurisdiction of<br><br>incorporation or organization) | (Commission File Number) | (I.R.S. Employer<br><br>Identification No.) |
| 3675 Market Street<br><br> <br>Philadelphia, Pennsylvania | 19104 | |
| --- | --- | |
| (Address of principal executive offices) | (Zip Code) |
Registrant’s telephone number, including area code:
(267) 817-5790
Not Applicable
(Former name or former address, if changed since last report)
Check the appropriate box below if the Form 8-K filing is intended to simultaneously satisfy the filing obligation of the registrant under any of the following provisions (see General Instruction A.2. below):
| ¨ | Written communications pursuant to Rule 425 under the Securities Act (17 CFR 230.425) |
|---|---|
| ¨ | Soliciting material pursuant to Rule 14a-12 under the Exchange Act (17 CFR 240.14a-12) |
| ¨ | Pre-commencement communications pursuant to Rule 14d-2(b) under the Exchange Act (17 CFR 240.14d-2(b)) |
| ¨ | Pre-commencement communications pursuant to Rule 13e-4(c) under the Exchange Act (17 CFR 240.13e-4(c)) |
Securities registered pursuant to Section 12(b) of the Act:
| Title of Each Class | Trading Symbol | Name of Exchange on Which Registered |
|---|---|---|
| Common Stock, par value $0.0001 per share | IPSC | Nasdaq Global Select Market |
Indicate by check mark whether the registrant is an emerging growth company as defined in Rule 405 of the Securities Act of 1933 (§230.405 of this chapter) or Rule 12b-2 of the Securities Exchange Act of 1934 (§240.12b-2 of this chapter).
Emerging growth company x
If an emerging growth company, indicate by check mark if the registrant has elected not to use the extended transition period for complying with any new or revised financial accounting standards provided pursuant to Section 13(a) of the Exchange Act. ¨
| Item8.01 | Other Events |
|---|
On December 16, 2021, Century Therapeutics, Inc. (the “Company”) updated information reflected in a slide presentation, which is attached as Exhibit 99.1 to this Current Report on Form 8-K and is incorporated herein by reference. Representatives of the Company will use the updated presentation in various meetings from time to time.
| Item 9.01 | Financial Statements and Exhibits |
|---|
(d) Exhibits
| ExhibitNo. | Document |
|---|---|
| 99.1 | Presentation of Century Therapeutics, Inc., dated December 16, 2021 |
| 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.
| CENTURY THERAPEUTICS, INC. | |
|---|---|
| By: | /s/ Osvaldo Flores, Ph.D. |
| Name: | Osvaldo Flores, Ph.D. |
| Title: | President and Chief Executive Officer |
Date: December 16, 2021
Exhibit 99.1
| VIRTUAL R&D UPDATE<br>December 16, 2021 |
|---|
| 2 2<br>FORWARD-LOOKING STATEMENTS<br>This presentation contains forward-looking statements within the meaning of, and made pursuant to the safe harbour provisions of, The Private Securities Litigation Reform Act of 1995. All statements<br>contained in this document, other than statements of historical facts or statements that relate to present facts or current conditions, including but not limited to, statements regarding possible or<br>assumed future results of operations, business strategies, research and development plans, regulatory activities, market opportunity, competitive position and potential growth opportunities are<br>forward-looking statements. These statements involve known and unknown risks, uncertainties and other important factors that may cause the our actual results, performance or achievements to be<br>materially different from any future results, performance or achievements expressed or implied by the forward-looking statements. In some cases, you can identify forward-looking statements by terms<br>such as “may,” “might,” “will,” “should,” “expect,” “plan,” “aim,” “seek,” “anticipate,” “could,” “intend,” “target,” “project,” “contemplate,” “believe,” “estimate,” “predict,” “forecast,” “potential” or “continue” or<br>the negative of these terms or other similar expressions. The forward-looking statements in this presentation are only predictions. We have based these forward-looking statements largely on our<br>current expectations and projections about future events and financial trends that we believe may affect the our business, financial condition and results of operations. These forward-looking<br>statements speak only as of the date of this presentation and are subject to a number of risks, uncertainties and assumptions, some of which cannot be predicted or quantified and some of which are<br>beyond our control, including, among others: our ability to successfully advance our current and future product candidates through development activities, preclinical studies, and clinical trials; our<br>reliance on the maintenance on certain key collaborative relationships for the manufacturing and development of our product candidates; the timing, scope and likelihood of regulatory filings and<br>approvals, including final regulatory approval of our product candidates; the impact of the COVID-19 pandemic on our business and operations; the performance of third parties in connection with the<br>development of our product candidates, including third parties conducting our future clinical trials as well as third-party suppliers and manufacturers; our ability to successfully commercialize our<br>product candidates and develop sales and marketing capabilities, if our product candidates are approved; and our ability to maintain and successfully enforce adequate intellectual property protection.<br>These and other risks and uncertainties are described more fully in the “Risk Factors” section of our most recent filings with the Securities and Exchange Commission and available at www.sec.gov. You<br>should not rely on these forward-looking statements as predictions of future events. The events and circumstances reflected in the our forward-looking statements may not be achieved or occur, and<br>actual results could differ materially from those projected in the forward-looking statements. Moreover, we operate in a dynamic industry and economy. New risk factors and uncertainties may emerge<br>from time to time, and it is not possible for management to predict all risk factors and uncertainties that we may face. Except as required by applicable law, we do not plan to publicly update or revise<br>any forward-looking statements contained herein, whether as a result of any new information, future events, changed circumstances or otherwise. |
| --- |
| 3 3<br>AGENDA<br>iPSC Cell Therapy Platform and Strategy<br>Lalo Flores, PhD, CEO<br>CNTY-101 Update<br>Hy Levitsky, MD, President of R&D<br>Treatment Paradigms and Unmet Need in B-Cell Malignancies<br>Eduardo Sotomayor, MD, Director of Cancer Institute at Tampa General Hospital<br>ELiPSE-1: CNTY-101 Phase 1 Trial<br>Nick Trede, MD, PhD, VP Early Clinical Development<br>Century iT Platform Update<br>Luis Borges, PhD, CSO<br>Q&A |
| --- |
| IPSC CELL THERAPY PLATFORM<br>AND STRATEGY<br>Lalo Flores ǀ CEO |
| --- |
| 5 5<br>CENTURY’S NEXT GENERATION iPSC TECHNOLOGY PLATFORM<br>Fully integrated discovery and development engine in place<br>Precision gene editing<br>Advanced manufacturing<br>Allo-Evasion™<br>Protein engineering<br>iPSC-derived NK cells iPSC-derived T cells<br>Comprehensive<br>allogeneic iPSC-<br>based cell<br>platform |
| --- |
| 6 6<br>CENTURY’S DIFFERENTIATED STRATEGY<br>CNTY-101<br>HLA-I<br>Knockout<br>IL-15<br>Safety<br>switch<br>HLA-II<br>Knockout<br>CD19 CAR<br>Allo-evasionTM edits<br>HLA-E<br> • CD19 targeted iNK product with best-in-class<br>potential<br> • First cell product candidate with 6 gene<br>edits introduced with CRISPR-HDR<br> • Incorporates Allo-evasion gene edits<br>designed to potentially prevent allo-<br>rejection and enable higher drug exposure<br>after multiple doses<br> • ELiPSE-1 Phase 1 study designed to maximize<br>learnings<br>CNTY-101 |
| --- |
| 7 7<br>CENTURY’S IPSC-DERIVED CAR-T PLATFORM \(CAR-IT\)<br> • Preclinical data supports decision to prioritize γδ iT<br>platform for first CAR-iT products<br> • γδ iT cells have potential for enhanced expansion<br>and trafficking to non-hematopoietic<br>compartments<br> • Preferred choice for solid tumor pipeline<br> • CNTY-102 will be Century’s first γδ iT product<br> • Potential to combine with CNTY-101 to address<br>unmet need in all types of B-cell malignancies<br> γδ iT Platform<br>CAR<br>TCR<br>Allo-Evasion<br>Gene edits<br>HLA-I<br>HLA-II<br>HLA-E<br>Homeostatic<br>cytokine<br>Undisclosed<br>CAR-iT |
| --- |
| 8 8<br>Product iPSC<br>Platform Targets Indications Ownership Expected IND<br>Submission Discovery Preclinical Phase 1 Phase 2 Phase 3<br>CNTY-<br>101 iNK CD19 B-Cell Malignancies Mid 2022<br>CNTY-<br>103 iNK CD133 +<br>EGFR Glioblastoma 2023<br>CNTY-<br>102 iT CD19 +<br>CD79b B-Cell Malignancies 2024<br>CNTY-<br>104 iNK Multi-<br>specific<br>Acute Myeloid<br>Leukemia 2024<br>Hematologic Tumors Solid Tumors<br>Product candidate pipeline across cell platforms<br>and targets in solid and hematologic cancers PIPELINE |
| --- |
| 9 9<br>ANTICIPATED 2022 R&D CATALYSTS<br> • CNTY-101: IND filing and Phase 1 start<br> • CNTY-103: Initiation of IND enabling activities<br> • Future pipeline candidates<br> • Disclosing multiple updates at medical and scientific congresses<br>throughout 2022<br>Pipeline<br>Platform |
| --- |
| CNTY-101 UPDATE<br>Hy Levitsky, MD ǀ President of R&D |
| --- |
| 11 11<br>Distinct Biology of NK cells vs T cells<br>Influence on Platform Development<br>NK vs T CELL BIOLOGY<br>Proliferative capacity T cell >> NK cell<br>Persistence/memory T cell >> NK cell<br>Pharmacokinetics Cmax and AUC after single dose: T cells > NK cells<br>Trafficking NK cell: lympho-hematopoietic compartment<br>T cell: all tissues<br>Toxicity Risks<br> • GVHD<br> • CRS/neurotoxicity<br> • On target toxicity<br> • GVHD: T cell > NK cell \(can be mitigated by editing\)<br> • CRS/neurotoxicity: T cell > NK cell<br> • On target/off tumor toxicity: T cell > NK cell \(persistence\) |
| --- |
| 12 12<br>NK CELL-BASED THERAPIES SHOW PROMISING EARLY<br>SIGNALS OF SAFETY AND EFFICACY IN R/R NHL<br>iC9/CAR.19/IL15<br>-Transduced<br>CB-NK GDA-201 FT516 FT596<br>Regimen - + IL-2<br>+ rituximab<br>+ anti-CD20 mAb<br>+ IL-2 Monotherapy + anti-CD20<br>mAb<br>CR, % 67% 65% 44%\* 30%\* 56%\*<br>CRS, all G \(G≥3\) No CRS No CRS No CRS 8% G1 11% G1-2<br>NE, all G \(G≥3\) No ICANS<br>\*≥ 90M cells<br> • Even in dose escalation, response rates are clinically meaningful<br> • Good safety profile<br> • Durability and impact of re-dosing to be determined |
| --- |
| 13 13<br>POTENTIAL ADVANTAGES OF REDOSING<br> • Experience with autologous CAR-T established the impact of “drug exposure” \(PK AUC\) on disease response<br> • Repeat dosing of CAR-iNK cells can extend drug exposure to achieve potentially deeper and more durable<br>remissions<br> • Infusion of fresh cells may mitigate cell exhaustion that limits single dose strategies<br> • Off the shelf availability of iPSC derived products enables a cyclical treatment paradigm common with most<br>other forms of cancer therapy<br>But only if initial dosing does not prime an allo-rejection response! |
| --- |
| 14 14<br>ALLO-EVASIONTM 1.0 DESIGNED TO OVERCOME 3 MAJOR<br>PATHWAYS OF HOST VS GRAFT REJECTION<br> β2M KO<br>\(HLA-I\)<br>HLA-E KI<br>CIITA<br>KO<br>\(HLA-II\)<br>CD8+<br>T Cell<br>CD4+<br>T Cell<br>NK cell<br>Deletion of<br> β<br>2M, a protein required to express<br>HLA-1 on the cell surface prevents recognition by<br>CD8 T cells<br>Knock out of CIITA eliminates HLA-II expression<br>to escape elimination by CD4 T cells<br>Knock-in of HLA-E prevents killing by NK cells<br>Core edits<br>Click to add text |
| --- |
| 15 15<br>ALLO-EVASIONTM 1.0 EDITS RENDER CELLS RESISTANT TO<br>T CELL AND NK CELL KILLING<br>Pan-HLA Class I<br>Primary blood NK<br>Unedited iNK<br> β2M KO \(Edited\) iNK<br>Isotype control stain<br>Donor 1 Donor 2<br>0<br>10<br>20<br>30<br>40<br>50<br><br>% Specific Cell Death<br> β2M KO iNK<br>HLA-E+ iNK<br>\*p<0.02<br>\*\*\*p<0.0001<br>N=5 healthy donors<br>\* \*\*\*<br><br>0<br>500<br>1000<br>1500<br>IFN-<br> γ<br> \(pg/mL\)<br><br>0<br>20<br>40<br>60<br>80<br>100<br>% Activated CD8 T cells<br>Allo iPSC-derived cell X<br>Eliminate<br>HLA-I<br>NK cell silencing<br>Express HLA-E |
| --- |
| 16 16<br>ILLUSTRATIVE POTENTIAL OF ALLO-EVASIONTM ON<br>CELLULAR PHARMACOKINETICS AND REPEAT DOSING<br>Repeat doses<br>With Allo-EvasionTM engineering<br>Without Allo-EvasionTM engineering<br>Time<br>Cell count<br>Initial dose<br>Minimum threshold to maintain<br>pharmacological pressure |
| --- |
| 17 17<br>INTRINSIC IL15 AND EXTRINSIC IL2 IMPROVE CAR-iNK PERSISTENCE<br>AND TUMOR CLEARANCE IN TISSUES \(LUNG\)<br>CAR-iNK<br>CAR/IL15-iNK<br>CAR-iNK<br>CAR/IL15-iNK<br>0.0<br>0.5<br>1.0<br>1.5<br>2.0<br>2.5<br><br>iNK cells \(% of live cells\)<br>Blood Lung<br>20 days<br>CD19CAR+IL15+iNK day 1<br>+/- rhIL2 days 1,3,5<br>Sampling day 7<br>+/- Transgenic IL15<br>Transgenic IL15<br>+/- Exogenous IL2<br>Transgenic IL15<br>+/- Exogenous IL2 |
| --- |
| 18 18<br>CNTY-101 DEMONSTRATES ROBUST TUMOR KILLING IN VITRO<br>AND IN VIVO<br>HLA-I<br>Knockout<br>IL-15<br>Safety<br>switch<br>HLA-II<br>Knockout<br>CD19 CAR CNTY 101<br>HLA-E<br>0 100 200<br>0<br>5×106<br>1×107<br>NALM-6 Lymphoma<br>Time Elapsed \(hours\)<br>RCU x<br> µ<br>m<br>2<br>/Well<br>CNTY-101 + NALM-6<br>NALM-6 Alone<br>0 5 10 15 20 25<br>0<br>2.0×10 8<br>4.0×10 8<br>6.0×10 8<br>8.0×10 8<br>1.0×10 9<br>1.2×10 9<br>Tumor Burden<br>Day Post-tumor Implantation<br>Average Radiance \(p/s/cm²/sr\)<br> ±<br> SEM<br>Tumor Alone<br>iPSC384 \(10e6 Fresh\)<br>iPSC384 \(15e6 Cryo\)<br>70% TGI, p=0.0029<br>62% TGI, p=0.0060<br>In vitro serial killing<br>In vivo xenograft<br>Tumor Growth Inhibition |
| --- |
| 19 19<br>SUMMARY<br> • CNTY 101 is Century’s first iPSC-derived NK cell therapy candidate for the treatment of CD19+ B cell<br>malignancies<br> • Incorporates a comprehensive gene editing strategy to evade CD4+ and CD8+ T cell and NK cell mediated<br>allo-rejection and have potentially favorable pharmacokinetics<br> • Product candidate designed to enable repeat dosing, potentially achieving greater drug exposure and<br>deeper and more durable clinical responses<br> • IND filing on track for mid 2022 |
| --- |
| Eduardo M. Sotomayor, MD<br>Director, TGH Cancer Institute<br>Professor, Morsani College of Medicine<br>University of South Florida<br>Treatment Landscape of Non-<br>Hodgkin’s Lymphomas:<br>It seems to be a crowded field…but it<br>depends how you see it and/or<br>approach it….. |
| --- |
| Timeline of Newer Agents for B-cell NHL<br>Ofatumumab<br> • First approved for CLL in 2009<br> • Extended treatment for recurrent or progressive CLL<br> • + Fludarabine and Cyclophosphamide for Relapsed CLL<br>Lenalidomide<br> • Relapsed MCL after ≥2 prior therapies<br>Ibrutinib<br> • MCL ≥ 1 prior therapies<br> • CLL/SLL, del\(17p\) CLL; +obinutuzumab for TN CLL<br> • WM \(+/- R\)<br> • MZL ≥ 1 prior anti-CD20 therapies<br>Obinutuzumab<br> • + Chlorambucil for TN CLL<br> • + Bendamustine for Rituximab-refractory FL<br> • +Chemo for TN FL<br> • +Ibrutinib for TN CLL<br>Idelalisib<br> • Relapsed CLL<br> • Relapsed FL or SLL after ≥ 2 prior therapies<br>2013 2014 2015 2016 2017 2018<br>Copanlisib<br> • FL ≥ 2 prior therapies<br>Tisagenlecleucel<br> • R/R large B-cell lymphoma ≥2nd prior therapies<br>Axicabtagene ciloleucel<br> • R/R large B-cell lymphomas ≥ 2 prior therapies<br>Venetoclax<br> • Del\(17p\) CLL≥ prior therapies<br> • +R for R/R CLL<br> • AML<br> • +Obinutuzumab for TN<br>CLL/SLL<br>Acalabrutinib<br> • CLL<br> • MCL ≥ 1 prior therapies<br>2019 2020<br>Zanubrutinib<br> • MCL ≥ 1 prior<br>therapies<br>Polatuzumab<br>Vedotin+BR<br>R/RDLBCL ≥ 2 prior<br>therapies<br>Duvelisib<br> • R/R CLL/SLL<br> • R/R FL<br>2021<br>Tafasitamab +<br>Lenalidomide<br> • Relapsed DLBCL<br>Axi-cel<br>R/R FL ≥ 2 prior<br>therapies<br>Liso-cel<br>R/R DLBCL ≥ 2<br>prior therapies<br>Zanubrutinib<br> • MZL<br> • WM<br>Loncastuximab<br>tesirine-lpyl<br>R/R DLBCL ≥ 2<br>prior therapies<br>Umbralisib<br>R/R MZL \(>1\)<br>FL >3 lines of<br>therapy<br>Brexucabtagene autoleucel<br> • Relapsed MCL<br>Tazemetostat<br>R/R FL with<br>EZH2 mutations<br>after ≥ 2 prior tx |
| --- |
| Targeted Therapy and Immunotherapy of B-cell NHL<br>Rituximab<br>Ofatumumab<br>Obinutuzumab<br>Polatuzumab vedotin<br>Loncastuximab tesirine<br>Tafasitamab \(MOR208\)<br>Ublituximab<br>Copanlisib<br>Duvelisib<br>Idelalisib<br>Umbralisib<br>Venetoclax<br>Ibrutinib<br>Acalabrutinib<br>Zanubrutinib<br>Pirtobrutinib<br>\(Loxo 305\)<br>Axi-cel / Liso-cel<br>Tisagenlecleucel<br>Brexucabtagene autoleucel Figure adapted from Crisci, et al. Front. Oncol. 2019. doi.org/10.3389/fonc.2019.00443<br>Tazemetostat<br>Lenalidomide<br>Pomalidomide |
| --- |
| • CD19 is an enticing target for novel approaches:<br> • Tafasitamab, anti-CD19 antibody \(+/- Lenalidomide\)<br> • Loncastuximab Tesirine \(Anti-CD19 Antibody-Drug Conjugate\)<br> • CD20 is….again an enticing target for bi-specific<br>antibodies:<br> • Several bi-specific directed T-cell engager \(BITE\) targeting CD20 and<br>CD3 \(CD20 x CD3\)….<br> • CD79b targeted ADC<br> • Does Polatuzumab vedotin change standard of care?<br>Immunotherapy: Targeting CD19 and CD20 \(Again…\) |
| --- |
| • Unlike the success in Hodgkin’s lymphoma, clinical trials with checkpoint<br>blockade antibodies in relapsed/refractory B-cell NHL have been disappointing so<br>far:<br> • Despite malignant B-cells being surrounded by an “army” of T-cells<br> • Role of the immunosuppressive Tumor Microenvironment \(TME\). TME is prognostic and<br>potentially predictive of outcomes in DLBCL1<br> • Perhaps frontline \(different setting\) checkpoint inhibition, given when host<br>immunity is relatively intact, might improve outcomes in DLBCL<br> • Indeed, it has been shown in the neoadjuvant setting for several solid malignancies…including<br>responses in subtypes not known to be sensitive to checkpoint blockade<br> • Anti-PDL1 \(Avelumab\) + Rituximab x 2 cycles in DLBCL \(Hawkes, E. et al 2020\)<br> • ORR of 60% with a CR of 21% suggest potential synergy and superior efficacy of<br>PDL1 inhibition in the frontline setting as compared to prior studies in the R/R<br>setting . Patients then went to receive standard R-CHOP with achievement of a CR<br>of 89%<br>Immunotherapy: Lessons learned from failures…<br>Checkpoint blockade…..perhaps setting is critical |
| --- |
| Glofitamab<br>ASH 2021.….the saga continues: Bispecific Antibodies |
| --- |
| “Game changer”: Bispecific antibodies<br>Human anti-CD20 x anti-CD3 Monoclonal Bispecific Antibody<br>Cross-linking results in targeted activation of local T-cells and T-cell-mediated<br>killing of CD20+ B-cells \(independently of TCR-mediated recognition\)<br>Cell lysis<br>T-cell CD20+<br>target cell<br>CH3<br>CH2<br>CH3<br>CH2<br>\*<br>CD20<br>binding<br>CD3/TCR<br>binding<br>ASH 2021<br>R/R Follicular lymphoma<br>Mosunetuzumab: ORR:80%, CR: 60%<br>Mosunetuzumab + Lena: ORR:89.7% CMR: 65.5%<br>Glofitamab: ORR: 81% CMR: 70%<br>Glofitamab+Obinutuzumab: ORR:100%,CMR: 74%<br>ASH 2021<br>R/R Mantle Cell Lymphoma<br>Glofitamab: ORR: 81% CMR: 67% |
| --- |
| Bi-Specific Antibodies: Safety<br>Antibody<br>CD20/CD3<br>Glofitamab Mosunetuzumab Odronextamab Epcoritamab<br>N 64 \( > 600 ug\) 131 136 58<br>CRS any<br>CRS >3<br>63.5%<br>3.8%<br>28.9%<br>1.1%<br>61%<br>7.3%<br>59%<br>0<br>NT any<br>NT >3<br>43.3%<br>NR<br>49%<br>1.1%<br>NR<br>3.6%%<br>6.9%<br>3.4%<br>CRS, cytokine release syndrome; NT, neurotoxicity |
| --- |
| • Autologous CD19 CAR T-cells have shown significant efficacy in<br>patients with relapsed/refractory CD19 positive DLBCL and other B-cell<br>lymphomas.<br> • Three platforms are FDA-approved \(Axi-cel, Tisa-cel and Liso-cel\) for DLBCL<br> • One platform approved for MCL \(Brexucabtagene autoleucel\)<br> • One platform approved for follicular lymphomas \(Axi-cel\)<br> • Cost, manufacture time, toxicity, progression while waiting for engineered T<br>cells. Mechanisms of resistance<br> • It is estimated that 30-40 percent of patients with large B-cell lymphoma might<br>be cured with CD19 CAR T-cells….<br> • Remaining 60 percent: Unmet need<br> • Moving CD19 CAR T cells into the first relapse setting:<br> • Is it better than autologous stem cell transplant for patients with DLBCL that<br>relapsed within 12 months of frontline chemoimmunotherapy?<br> • ASH 2021: ZUMA-7, TRANSFORM and BELINDA Trials<br>Immunotherapy: Targeting CD19 in B-cell lymphomas<br>Successes, Failures and Opportunities |
| --- |
| ASH 2021: Will CD19 CAR T-cell Replace Autologous<br>transplant for DLBCL?<br>ZUMA-7<br>ASH 2021: Axi-cel<br>BELINDA<br>Tisagenlecleucel<br>High-risk DLBCL:<br>.. Refractory to first-line tx<br>.. Relapsed after first-line tx<br>CAR T-cell therapy<br>Salvage therapy/<br>auto-transplant<br>NCT03391466. NCT03570892. NCT03575351.<br>Positive: CAR T-cells<br>better than ASCT<br>No differences<br>TRANSFORM<br>ASH 2021: Liso-cel |
| --- |
| Bispecific Antibodies vs. Autologous CAR T-Cells<br>T<br>Tumor<br>cell<br>Characteristic Bispecific Antibodies CAR T-Cell Therapy<br>Preparation “Off the shelf” In vitro manufacturing \(3-4 wks\)<br>Dosing Repetitive Single \(following lymphodepleting CT\)<br>CRS incidence Less Greater<br>T<br>Bispecific antibody<br>Cytotoxic T lymphocyte<br>T<br>CAR T Cell |
| --- |
| • Novel targeted agents either alone or in combination are improving clinical<br>outcomes of patients with B-cell lymphomas, mainly in the<br>relapsed/refractory setting<br> • Some of them have been \(or are being\) evaluated as frontline therapy alone<br>or in combination in some B-cell malignancies \(CLL/SLL; MCL\)<br> • Overall, improvement in PFS, minimal impact in OS<br> • Many patients either do not respond to targeted agents \(innate resistance\)<br>or, after an initial response they progress \(acquired resistance\).<br> • Room for additional targeted therapies……….<br>Targeted Therapy: Many successes…but also limitations |
| --- |
| Unmet needs + Good Science = Opportunities in a<br> “crowded” Therapeutic Landscape<br>I. Good Science:<br>- Beyond T-cell immunotherapies… Harnessing Innate Immunity<br>- Genetically engineered NK cells<br>- Genetically engineered Macrophages<br>II. Unmet Needs in Non-Hodgkin’s lymphomas<br>- Difficult to treat lymphomas:<br>- Double/triple hit large B cell lymphomas<br>- POD24 low grade lymphomas<br>- MCL with p53 abnormalities<br>- Transformed lymphomas<br>- Primary CNS lymphomas<br>- Viral-associated lymphomas |
| --- |
| II. Emerging Needs in Non-Hodgkin’s lymphomas<br>- Innate or acquired resistance to novel agents<br>- BTK resistance \(MCL, CLL, WM, MZL\)<br>- CD19 CAR T-cells \(DLBCL, MCL, FL\)…. CLL<br>- Double refractory \(FL, MCL\)<br>Unmet needs + Good Science = Opportunities in a<br> “crowded” Therapeutic Landscape<br>III. “Wide open” lymphomas for…..novel therapies<br>- T-cell/NK malignancies<br>- Viral-associated lymphomas<br>- CNS lymphomas |
| --- |
| ASH 2021:“Off the Shelf” Engineered Cellular Products:<br>Allogeneic Therapies<br>Advantages<br> • Eliminates the manufacturing time and<br>allows true point of care administration<br> • Expand access to therapy \(ie,<br>leukopenic patients\)<br> • Improve safety through genetic<br>manipulation<br> • Can scale to much larger numbers with<br>broader impact for those in need \(not<br>achievable with the generation of an<br>autologous product for each patient\)<br>Requirements<br> • Should not induce GvHD<br> • Should not result in immune rejection of<br>cellular product<br> • Immediately available<br> • Precise genetic engineering<br>Modified from Crooks, G.M. ASH 2020 |
| --- |
| ASH 2021: Sources of Allogeneic Cells<br>Pluripotent stem cells<br> • iPSC \(inducible pluripotent stem<br>cells\)<br> • T-iPSC \(T\)<br>- Self-renewing. Expanded indefinitely<br>Homogenous product available in large<br>batches<br>-Complex editing is possible<br>-Complex differentiation process is a<br>challenge<br>Modified from Crooks, G.M. ASH 2020<br>Healthy Donor<br> • Peripheral Blood \(T-cells\)<br> • Umbilical Cord \(NK cells\)<br>- Mature cells<br>- Multiple products per donation \(up to 100<br>products\)<br>-Non-self renewing<br>-Heterogenous starting product makes<br>consistency challenging |
| --- |
| Conclusions<br> • Despite the progress that has been made in the treatment of NHL,<br>there are still several unmet needs<br> • Emerging needs as a result of changing treatment landscape<br> • ie resistance to targeted/immune based therapies<br> • Strategies to harness innate immunity represent a compelling<br>opportunity to address these gaps<br> • Potential for off-the-shelf engineered cell therapies |
| --- |
| esotomayor@tgh.org<br>THANK YOU ! |
| --- |
| CNTY-101 PHASE I TRIAL DESIGN<br>Nick Trede, MD, PhD ǀ VP Early Clinical Development |
| --- |
| 39 39<br>CNTY-101: AN ALLOGENEIC, iPSC-DERIVED CAR-iNK PRODUCT<br>CANDIDATE TARGETING CD19 FOR R/R B-CELL MALIGNANCIES<br>CNTY-101 has the potential to change the lymphoma<br>patient treatment paradigm<br> • Potentially treat patients immediately upon<br>diagnosis<br> • Based on Allo-evasion and anticipated ability to give<br>additional cycles of treatment, potential to enhance<br>depth and durability of response<br> • Potential to avoid lymphodepletion with additional<br>treatment cycles due to reduced alloreactivity, and<br>engineered IL-15 to potentially improve the safety<br>profile<br> • Availability of CNTY-101 off-the-shelf potentially<br>enables outpatient use at any clinical site, improving<br>patient access<br>CNTY-101<br>HLA-I<br>Knockout<br>IL-15<br>Safety<br>switch<br>HLA-II<br>Knockout<br>CD19 CAR<br>Allo-evasionTM edits<br>HLA-E |
| --- |
| 40 40<br>THE ELIPSE-1 STUDY: A PHASE 1, MULTICENTER, OPEN-LABEL STUDY OF CNTY-101 IN<br>SUBJECTS WITH RELAPSED OR REFRACTORY CD19 POSITIVE B CELL MALIGNANCIES<br>- KEY SELECTION CRITERIA<br>INCLUSION CRITERIA<br> • Aggressive NHL: DLBCL, HGBL, PMBCL MCL,<br>tFL, FL3B<br> • Indolent NHL: FL, MZL<br> • At least 2 prior lines of therapy, including<br>anthracycline \(or alkylator for iFL\) and anti-<br>CD20 antibody<br> • Patients who have already undergone<br>or are unable to undergo CAR T<br>therapy are eligible<br> • ECOG score of 0 or 1<br> • Adequate organ function<br> • Willing to undergo required biopsies<br>EXCLUSION CRITERIA \(cannot meet any\)<br> • CNS-only disease<br> • Prior allo stem cell transplant<br> • Recent other malignancies<br> • Ongoing infections<br> • Cardiac insufficiency<br> • CNS pathology<br> • COVID infection \(by PCR test\) within 10 days<br>\(mild/asymptomatic\) or 20 days<br>\(severe/critical\). Symptoms must have<br>resolved.<br> • COVID vaccine within 14 days<br>For outpatient treatment \(preferred\) patients<br>have to stay within 60 minutes of the site<br>\(hotel accommodation will be provided\)<br>The design of the EliPSE-1 clinical trial is subject to FDA review and approval and may be changed prior to the commencement of the trial. |
| --- |
| 41 41<br>ELiPSE-1 OBJECTIVES<br>Primary<br>Maximum-tolerated dose \(MTD\) or maximum administered dose regimen of CNTY-101<br>\(dose and schedule of CNTY-101 with IL-2\)<br>Recommended phase 2 regimen \(RP2R\) of CNTY-101 + IL-2<br>Secondary<br>Antitumor activity<br>PK profile<br>Safety and tolerability at RP2R<br>Time to dosing<br>Exploratory<br>Feasibility of additional treatment cycles<br>PD parameters; immune responses; biomarkers<br>The design of the EliPSE-1 clinical trial is subject to FDA review and approval and may be changed prior to the commencement of the trial. |
| --- |
| 42 42<br>TIMELINE \(SINGLE DOSE\) AND ASSESSMENTS<br>LTFU<br>Study<br>Lymphode<br>pletion<br>Efficacy<br>assessment<br>D28 D1<br>CNTY-101<br>infusion<br>IL2 infusion<br>daily<br>Screening, enrollment<br>Safety evaluation period<br>Frequent visits & safety<br>assessments<br>M4 M7 M10 M13 M19 M24<br>SAFETY: CONTINUOUS ASSESSMENT<br> • Dose-limiting toxicities<br> • Incidence and nature of adverse events \(AEs\)<br>and SAEs<br>EFFICACY<br> • PET and CT scans<br> • Response assessed using the Lugano<br>criteria<br>PK<br> • Both molecular and flow on blood samples<br>PD/BIOMARKERS<br> • Immunogenicity of CNTY-101<br> • Hypogammaglobulinemia<br> • Assessment of tumor microenvironment,<br>cytokines<br>PET/CT<br>The design of the EliPSE-1 clinical trial is subject to FDA review and approval and may be changed prior to the commencement of the trial. |
| --- |
| 43<br>CNTY-101 EXPLORATORY STUDIES WITHIN ELIPSE-1<br>r<br>1<br>5<br>,<br>2<br>0<br>2<br>1<br>3<br>CRP<br>IL<br>-<br>15<br>% VAF<br>Lymphodepletion,<br>Century product<br>infusion<br>CNTY-101<br>Blood<br>Serum/ Plasma<br>Tumor Biopsy<br>Mechanism of Action/<br>Resistance<br>Safety & Other<br>Efficacy Correlates<br>Pharmacokinetics:<br>Expansion &<br>Persistence<br>Phenotype &<br>function<br>Homeostatic cytokines,<br>IL-2<br>Minimum residual disease<br>\(ctDNA\)<br>iNK tumor<br>Trafficking<br>Tumor Antigen expression<br>Tumor immune microenvironment<br>Tumor Biology<br>Tumor burden and<br>other baseline<br>biomarkers<br>PD biomarkers/<br>B cell aplasia<br>Cellular<br>Immunogenicity<br>Humoral<br>Immunogenicity<br>Cytokines:<br>CRS,<br>neurotoxicity<br>The design of the EliPSE-1 clinical trial is subject to FDA review and approval and may be changed prior to the commencement of the trial. |
| --- |
| 44 44<br>ELiPSE-1 TREATMENT SCHEMA<br>\(1\) EVALUATION OF SINGLE DOSE ESCALATION AND IL-2<br>Part 1<br>With IL-2<br>30e6<br>x1<br>Schedule A<br>100e6<br>x1<br>1000<br>e6 x1<br>300e6<br>x1<br>100e6<br>x1<br>Dose Level \(DL\)<br>Fallback Dose<br>Starting Dose<br>DL-1<br>DL1<br>DL2<br>DL3<br>No IL-2<br>Safety Review Committee<br>reviews data and<br>implements dosing<br>decisions<br>First 1 to 3 patients<br>without IL-2, then<br>supplement for 8 days<br>following CNTY-101 dose<br>The design of the EliPSE-1 clinical trial is subject to FDA review and approval and may be changed prior to the commencement of the trial. |
| --- |
| 45 45<br>ELiPSE-1 TREATMENT SCHEMA<br>\(2\) EVALUATION OF ADDITIONAL CYCLE\(S\)<br>Safety Review Committee<br>reviews data and<br>implements dosing<br>decisions Part 1<br>With IL-2<br>30e6<br>x1<br>Schedule A<br>100e6<br>x1<br>1000<br>e6 x1<br>300e6<br>x1<br>Redosing for patients<br>who demonstrate clinical<br>benefit post-FDA<br>approval<br>Dose Level \(DL\)<br>Fallback Dose<br>Starting Dose<br>DL-1<br>DL1<br>DL2<br>DL3<br>100e6<br>x1<br>+/-<br>First 1 to 3 patients<br>without IL-2, then<br>supplement for 8 days<br>following CNTY-101 dose<br>\( \)<br>The design of the EliPSE-1 clinical trial is subject to FDA review and approval and may be changed prior to the commencement of the trial. |
| --- |
| 46 46<br>ELiPSE-1 TREATMENT SCHEMA<br>\(3\) EVALUATION OF MULTIPLE DOSING SCHEDULE<br>Schedule B opens once<br>MTD or max dose in<br>Schedule A is<br>determined.<br>Starting Schedule B Dose:<br>1/3 current dose, given 3<br>times, 1 week apart<br>Part 1<br>With IL-2<br>Part 2<br>Dose Level \(DL\)<br>30e6<br>x1<br>Schedule A<br>100e6<br>x1<br>1000 e6<br>x1<br>300e6<br>x1<br>RP2R<br>To N=20<br>subjects\*<br>100e6<br>q w x3<br>1000e6<br>q w x3<br>300e6<br>q w x3<br>Schedule B<br>Fallback Dose<br>Starting Dose<br>DL-1<br>DL1<br>DL2<br>DL3<br>\* Including subjects from Part 1<br>100e6<br>x1<br>No IL-2<br>Safety Review Committee<br>reviews data and<br>implements dosing<br>decisions<br>Redosing for patients<br>who demonstrate clinical<br>benefit post-FDA<br>approval<br>First 1 to 3 patients<br>without IL-2, then<br>supplement for 8 days<br>following CNTY-101 dose<br>The design of the EliPSE-1 clinical trial is subject to FDA review and approval and may be changed prior to the commencement of the trial. |
| --- |
| 47 47<br>ELiPSE-1 TREATMENT SCHEMA<br>\(4\) KEY MILESTONES<br>Schedule B opens once<br>MTD or max dose in<br>Schedule A is<br>determined.<br>Starting Schedule B Dose:<br>1/3 current dose, given 3<br>times, 1 week apart<br>Part 1<br>With IL-2<br>Part 2<br>Dose Level \(DL\)<br>30e6<br>x1<br>Schedule A<br>100e6<br>x1<br>1000 e6<br>x1<br>300e6<br>x1<br>RP2R<br>To N=20<br>subjects\*<br>100e6<br>q w x3<br>1000 e6<br>q w x3<br>300e6<br>q w x3<br>Schedule B<br>Fallback Dose<br>Starting Dose<br>DL-1<br>DL1<br>DL2<br>DL3<br>\* Including subjects from Part 1<br>100e6<br>x1<br>No IL-2<br>Safety Review Committee<br>reviews data and<br>implements dosing<br>decisions<br>Redosing for patients<br>who demonstrate clinical<br>benefit post-FDA<br>approval<br>First 1 to 3 patients<br>without IL-2, then<br>supplement for 8 days<br>following CNTY-101 dose<br> • IND submission mid 2022<br> • FPFV 2H2022<br> • Approximately 45 patients<br>The design of the EliPSE-1 clinical trial is subject to FDA review and approval and may be changed prior to the commencement of the trial. |
| --- |
| 48 48<br>SUMMARY<br> • Century's iPSC-derived NK cell therapies - CNTY-101<br> • Precise, multiple genome edits<br> • Unlimited supply<br> • Homogeneous product<br> • Off-the-shelf<br> • Allo-evasion<br> • Potential for excellent safety profile and outpatient treatment<br> • Potential for promising efficacy, access to redosing and re-treatment cycles<br>ELiPSE-1<br>ELiPSE-1<br>ELiPSE-1 |
| --- |
| CENTURY IT PLATFORM UPDATE<br>Luis Borges, PhD ǀ CSO |
| --- |
| 50 50<br>AT CENTURY, WE ENGINEER iPSCs TO GENERATE iT AND<br>iNK CELL CANCER THERAPIES<br> • CAR-TCR<br> • Allo-evasionTM<br> • TME modulation<br> • Safety<br> • Consistency<br> • Yield<br> • Fitness<br>Candidate Generation Manufacturing<br>iPSC<br>Engineered iPSC<br>MCB<br>Gene editing & cell engineering<br>Process optimization & scale up<br>iNK cell<br>iT cell<br>\(Induced Pluripotent Stem Cells\) |
| --- |
| 51 51<br>CENTURY’S iT CELL PLATFORM<br>THE CONCEPT OF TrueT CELLS EXPRESSING TRUSTED TCRs<br>T cells express two major types of TCRs<br> • αβ TCRs: recognize hypervariable peptide antigens in the<br>context of MHC molecules; responsible for GvHD<br> • γδ TCRs; recognize invariant antigens such as phospho-<br>antigens independently of MHC molecules; no GvHD<br>TrueT cells express Trusted TCRs<br> • Trusted TCRs do not to induce GvHD<br> • γδ TCR<br> • Shared viral-specific αβ TCRs<br> • Trusted TCRs improve iPSC T cell differentiation and might<br>improve in vivo persistence and functionality<br>CAR<br>TCR<br>TrueT cells |
| --- |
| 52 52<br> γδ T CELLS SHARED PROPERTIES OF ADAPTIVE AND INNATE IMMUNE<br>CELLS AND OFFER UNIQUE ADVANTAGES FOR CANCER THERAPY<br>Property αβ T cells γδ T cells<br>Low risk of GvHD -<br>Innate anti-tumor killing -<br>TCR-mediated tumor killing<br>MHC-independence for TCR-<br>mediated killing<br>-<br>Recognition of molecular<br>patterns of tumor cell distress<br>-<br>Low risk of CRS - |
| --- |
| 53 53<br>CENTURY HAS GENERATED MULTIPLE TiPSC LINES<br>THROUGH THE REPROGRAMING OF γδ T CELLS<br>CD3+ TCRgd+ Vg9+ Vd1+ Vd2+<br>0<br>25<br>50<br>75<br>100<br>Percent<br>Day 0<br>Day 7<br>Day 9<br>Day 12<br>Day 14<br>Expansion Of γδ T Cells From Blood<br>TiPSC Colonies Derived<br>From γδ T Cells |
| --- |
| 54 54<br>CENTURY HAS DEVELOPED HIGHLY REPRODUCIBLE<br>PROTOCOLS TO DIFFERENTIATE γδ TiPSC LINES<br>CD34<br>CD43 CD45 CAR<br>Side scatter<br>0<br>50<br>100<br>Day<br>% of cells expressing<br>0 7 14 21 28<br>CD34 CD45<br>CD3/TCRγδ<br>CD7<br>98% CAR+<br>cells<br>~100% TCR+<br> γδ iT cells |
| --- |
| 55 55<br> γδ CAR-iT CELLS KILL TUMORS AS EFFICIENTLY OR<br>BETTER THAN CAR-T CELLS<br>0 20 40 60 80<br>0<br>20<br>40<br>60<br>80<br>100<br>Time \(hours\)<br>Normalized Target count<br>\(% of cell line alone control\)<br>0 20 40 60 80<br>0<br>20<br>40<br>60<br>80<br>100<br>Time \(hours\)<br>Normalized Target count<br>\(% of cell line alone control\)<br><br><br><br>NALM-6 Lymphoma<br>\(CD19Hi\)<br>Reh Lymphoma<br>\(CD19Low\)<br> γδ CAR-iT Cells Kill Multiple Lymphoma Cell lines Expressing Different Levels Of CD19<br>T cells from 3<br>healthy donors |
| --- |
| 56 56<br> γδ CAR-iT CELLS KILL LYMPHOMA CELLS THROUGH MULTIPLE<br>ROUNDS OF KILLING WITHOUT REACHING EXHAUSTION<br>0 100 200 300<br>0<br>500000<br>1000000<br>1500000<br>2000000<br>2500000<br>Time Elapsed \(hours\)<br>Red object total area \(<br> μ<br>m<br>2<br>/image\)<br><br><br><br><br>0 100 200 300<br>0<br>500000<br>1000000<br>1500000<br>2000000<br>2500000<br>Time Elapsed \(hours\)<br>Red object total area \(<br> μ<br>m<br>2<br>/image\)<br><br><br><br><br><br> γδCAR-iT<br>CAR-T A<br>CAR-T B<br>CAR-T C<br>Serial Killing CD19+ Lymphoma Cells<br>+ IL-2<br>+ IL-15<br>T cells from 3<br>healthy donors |
| --- |
| 57 57<br> γδ CAR-iT CELLS DO NOT RELEASE INFLAMMATORY CYTOKINES WHEN<br>KILLING TARGETS<br><br><br> γδCAR-iT<br>CAR-T A<br>CAR-T B<br>CAR-T C<br>IFN-γ<br>T cells from 3<br>healthy donors<br>5:1 1:1 1:5 Target Alone<br>0<br>500<br>1000<br>1500<br>2000<br><br>Killing Asasy E:T Ratio<br>IFN-<br> γ<br> \(pg/ml\)<br>5:1 1:1 1:5 Target Alone<br>0<br>50<br>100<br>150<br><br>Killing Asasy E:T Ratio<br>TNF \(pg/mL\)<br>TNF<br>Unlike Conventional CAR-T Cells, γδ CAR-iT Cells Did Not Release<br>IFN-γ Or TNF When Interacting With Tumors Cells |
| --- |
| 58 58<br>CENTURY’S CAR-γδ iT CELLS HAVE ROBUST<br>ANTI-LYMPHOMA ACTIVITY IN VIVO<br>0<br>2×108<br>4×108<br>6×108<br>8×108<br>1×109<br>1.2×109<br>Day Post-tumor Implantation<br>Average Radiance \(p/s/cm²/sr\)<br> ±<br> SEM<br>21 0 7 14<br>Tumor Burden<br>1 dose on day 1<br>3 doses on days<br>1, 8, and 15<br>Control tumor<br>only<br>NALM-6 Lymphoma Xenograft |
| --- |
| 59 59<br>NEXT STEPS<br> • Complete the reprograming of clinical grade γδ<br>TiPSC lines from multiple donors<br> • Engineer core features on novel γδ T-IPSC lines to<br>generate a common TiPSC progenitor for multiple<br>iT cell product candidates<br> • Generate new iT product candidates for solid<br>tumors and heme malignancies<br> γδ iT Product Candidates Will Include<br>Multiple Gene Edits<br>CAR<br>TCR<br>Allo-Evasion<br>Gene edits<br>HLA-I<br>HLA-II<br>HLA-E<br>Homeostatic<br>cytokine<br>Undisclosed |
| --- |
| 60 60<br>CENTURY’S iPSC-DERIVED γδ T CELLS IN ACTION |
| --- |
| THANK YOU |
| --- | | Q&A | | --- |