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  • 1
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    204 KSQ-004: Unbiased pair-wise discovery of SOCS1 and Regnase-1 as the top CRISPR/Cas9 dual-edit combination enhancing in vivo TIL potency against solid tumors
    BMJ ; 2021
    In:  Journal for ImmunoTherapy of Cancer Vol. 9, No. Suppl 2 ( 2021-11), p. A215-A215
    Details
    In: Journal for ImmunoTherapy of Cancer, BMJ, Vol. 9, No. Suppl 2 ( 2021-11), p. A215-A215
    Abstract: The application of CRISPR/Cas9-gene-editing to enhance the anti-tumor activity of T cell Adoptive Cell Therapies (ACT) is a promising approach in the treatment of patients with solid tumors. We developed an in vivo CRISPR^2 screening approach and interrogated the top dual-edit combinations enhancing T cell anti-tumor function. We discovered that across all possible dual-edit combinations of T cell targets, inactivation of Regnase-1 and SOCS1 led to the greatest enhancement in anti-tumor T cell potency in vivo. We applied these findings to discover KSQ-004, a Regnase-1/SOCS1 dual-edited human CRISPR/Cas9-engineered TIL (eTIL) therapy currently under development for therapeutic use. Methods We generated randomly paired CRISPR guide libraries (CRISPR2) targeting top hits from previous single-gene Immune CRISPRomics® screens. CRISPR^2 libraries with over 1200 gene pairs were screened in primary mouse OT1 and PMEL-TCR-Tg-T cells in the relevant syngeneic tumor models. Top dual-edit combinations were then evaluated in the immunotherapy-refractory B16F10 metastatic lung tumor model. The efficacy of the top combo was further evaluated in a mouse TIL model wherein TIL from B16-Ova tumors were expanded and engineered ex vivo and adoptively transferred into tumor bearing hosts for efficacy assessment. Results Of the 1200+ combinations tested in the CRISPR^2 screens, the Regnase-1/SOCS1 combination ranked amongst the top dual-edits, with this combination enhancing T cell infiltration into tumors 〉 3500-fold in comparison to controls. Studies conducted in the checkpoint therapy refractory B16F10 lung metastasis model revealed that Regnase-1/SOCS1 dual-edited PMEL-TCR-Tg-T cells conferred remarkable survival benefit relative to controls, significantly extending median survival of animals from 21 days to 53 days. Furthermore, Regnase-1+SOCS1-edited mouse TIL isolated and expanded from B16-Ova tumors exerted complete control of tumors upon re-infusion into hosts, suggesting rejuvenation of tumor-experienced TILs by this edit combination. To apply these insights for therapeutic use, we discovered KSQ-004, a human Regnase-1/SOCS1 dual-edited CRISPR/Cas9-engineered TIL (eTIL). Methods were developed to manufacture KSQ-004 from melanoma and NSCLC tumor samples, with eTIL demonstrating robust expansion and viability comparable to unedited control TIL with over 90% knockout of both targets. Importantly, KSQ-004 produced elevated IFNγ upon autologous tumor stimulation and exerted greater control of tumor spheroids in vitro. Conclusions We used a novel CRISPR^2 screen approach to identify Regnase-1/SOCS1 as the top dual edit combination enhancing T cell function in the tumor microenvironment. We translated these findings to therapeutic use with the discovery of KSQ-004, a dual-edited eTIL therapy engineered that possesses enhanced anti-tumor potency and persistence against solid tumors.
    Type of Medium: Online Resource
    ISSN: 2051-1426
    URL: Article
    DOI: 10.1136/jitc-2021-SITC2021.204
    Language: English
    Publisher: BMJ
    Publication Date: 2021
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    Abstract 1337: Functional genomic characterization of the USP1 inhibitor KSQ-4279 reveals a distinct mechanism of action and resistance profile relative to other DDR targeting drugs
    American Association for Cancer Research (AACR) ; 2021
    In:  Cancer Research Vol. 81, No. 13_Supplement ( 2021-07-01), p. 1337-1337
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 81, No. 13_Supplement ( 2021-07-01), p. 1337-1337
    Abstract: Genomic instability is a hallmark of most cancers that enables tumor cells to adapt and evolve, but also creates vulnerabilities that can be therapeutically exploited. Cancer therapies that target the DNA Damage Response (DDR) have proven to be efficacious across a broad range of cancer types, but often present a narrow therapeutic window and limited duration of response due to the development of resistance. Through mining our proprietary CRISPRomics® Oncology dataset we identified the ubiquitin protease, USP1, as an attractive target with activity in ovarian and triple negative breast cancers (TNBC). USP1 facilitates DNA repair via its role regulating the Fanconi anemia complex and translesion synthesis. We developed a series of potent, selective USP1 inhibitors to investigate the therapeutic potential of targeting USP1 in tumor settings dependent on those DNA repair processes. When profiled across a broad range of cancer cell line models, the USP1-inhibitor KSQ-4279 showed anti-proliferative effects in a subset of cell lines, often characterized by the presence of homologous recombination deficiencies (HRD), including mutations in BRCA1/2. To better understand the mechanism of action of KSQ-4279, we employed large scale functional genomic screens using KSQ-4279, olaparib, and cisplatin, in combination with a DNA-repair focused CRISPR library, to identify genetic determinants of sensitivity and anticipate modes of drug resistance. In addition to recovering genetic associations between KSQ-4279 and genes that modify USP1's direct substrates, our screens identified genetic interactions of KSQ-4279 with multiple DNA repair pathways, including genes involved in ubiquitin-mediated signaling events that regulate the response to DNA damage and replication stress. These studies revealed that the profile of resistance to KSQ-4279 is distinct from, and in some cases complementary to, other DNA damaging agents, and provide a mechanistic rationale for the use of KSQ-4279 in combination with other agents that target DNA repair. Consistent with the largely non-overlapping resistance profile of USP1 and PARP inhibitors, we found that the combination of KSQ-4279 with olaparib was able to induce strong and durable regressions across a number of ovarian and TNBC PDX models. Citation Format: Sol Shenker, Hugh Gannon, Alyssa Carlson, Paula Grasberger, Pamela Sullivan, Chris Middleton, Anne Dodson, Caroline Bullock, Michael McGuire, Erica Tobin, Kerstin Sinkevicius, Mike Schlabach, Frank Stegmeier, Louise Cadzow, Andrew Wylie. Functional genomic characterization of the USP1 inhibitor KSQ-4279 reveals a distinct mechanism of action and resistance profile relative to other DDR targeting drugs [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1337.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2021-1337
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2021
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    Abstract 2175: KSQ-001: A CRISPR/Cas9-engineered tumor infiltrating lymphocyte (eTILTM) therapy for solid tumors
    American Association for Cancer Research (AACR) ; 2020
    In:  Cancer Research Vol. 80, No. 16_Supplement ( 2020-08-15), p. 2175-2175
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 80, No. 16_Supplement ( 2020-08-15), p. 2175-2175
    Abstract: Adoptive cell therapy (ACT) with ex vivo expanded tumor infiltrating lymphocytes (TIL) offers a potentially transformative treatment for treatment refractory solid tumors. However, the immunosuppressive tumor microenvironment (TME) limits the effectiveness of TIL therapy. To systematically identify targets that have the potential to improve T-cell function in the TME, we conducted two genome-wide CRISPR/Cas9 functional screens of immune cells using our proprietary CRISPRomics® platform. The first screen employed primary mouse T cells and assessed in vivo T cell infiltration into tumors by measuring sgRNA guide enrichment. Notably, this screen identified clinically active targets, such as PD-1, and identified multiple targets, including Cell Therapy-1 (CT-1), that demonstrated anti-tumor T-cell function superior to PD-1. The potential of inactivating CT-1 for ACT was subsequently validated in both PD-1 sensitive and insensitive syngeneic tumor models in the absence of any additional conditioning regimens. CT-1 edited T cells established durable anti-tumor memory characterized by a T central memory state. A second genome-wide screen employed human TIL and assessed the impact of gene inactivation on human TIL expansion under standard manufacturing conditions. This screen also identified CT-1 as a top target. We therefore prioritized the development of KSQ-001, an engineered TIL (eTILTM) therapy, created via CRISPR/Cas9-mediated editing of CT-1. Potent and selective sgRNAs targeting CT-1 were identified and characterized, and manufacturing methods to engineer human TIL with high efficiency have been developed. Together, these data demonstrate that our CRISPRomics® platform enables comprehensive target identification and validation of compelling new targets for the development of robust eTILTM therapies, and support the clinical evaluation of KSQ-001 as a next generation adoptive cell therapy in a variety of treatment-refractory solid tumors. Citation Format: Mike Schlabach, Nick Colletti, Anja Hohmann, Christopher Wrocklage, Hugh Gannon, Alejandra Falla, Noah Tubo, Robert A. LaMothe, Caroline Bullock, Pete T. Mitchell, Nafeeza Hafeez, Suphinya Sathithloetsakun, Paula E. Grasberger, Isabelle Le Mercier, Tracy E. Garrett, Sean Keegan, Sol Shenker, Charlotte Franco, Frank Stegmeier, Gregory V. Kryukov, Louise Cadzow, Micah Benson. KSQ-001: A CRISPR/Cas9-engineered tumor infiltrating lymphocyte (eTILTM) therapy for solid tumors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2175.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2020-2175
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2020
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  • 4
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    Abstract 1581: KSQ-4279, a first-in-class USP1 inhibitor shows strong combination activity with multiple PARP inhibitors in BRCA mutant cancers
    American Association for Cancer Research (AACR) ; 2023
    In:  Cancer Research Vol. 83, No. 7_Supplement ( 2023-04-04), p. 1581-1581
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 83, No. 7_Supplement ( 2023-04-04), p. 1581-1581
    Abstract: Tumors harboring BRCA1/2 mutations and other homologous recombination deficiencies are sensitive to agents targeting pathways involved in DNA repair including poly (ADP-ribose) polymerase (PARP) inhibitors, which have been approved for the treatment of BRCA mutant cancers. Despite the clinical benefit with these drugs, many patients achieve incomplete disease control and often develop resistance. By employing our CRISPRomics® technology to screen over 600 cancer cell lines, we identified the deubiquitinating enzyme USP1 as one of the top targets that displays selective anti-tumor activity in ovarian and triple negative breast cancers with homologous recombination deficiencies. Subsequent drug discovery efforts identified KSQ-4279 as a potent and highly selective first-in-class small molecule USP1 inhibitor that is now in clinical development. In preclinical models, we previously demonstrated that KSQ-4279 shows therapeutic potential in combination with olaparib for treating patients who are either intrinsically resistant, or have developed acquired resistance to PARP inhibitors. We performed studies to investigate the therapeutic potential of combining KSQ-4279 across a variety of PARP inhibitors with different ‘PARP trapping’ potencies. Clonogenic assays demonstrated synergistic effects of KSQ-4279 across multiple PARP inhibitors regardless of their PARP trapping potency. Second generation PARP1 selective inhibitors such as AZD5305 are currently in clinical development and may provide a safety and efficacy advantage for patients. We have investigated the potential of combining KSQ-4279 with AZD5305 in a PARP refractory patient-derived triple negative breast cancer (TNBC) xenograft model by evaluating tolerability and anti-tumor efficacy. We observed significantly greater and more durable anti-tumor activity, including regressions, with the combination therapy compared to single agents. Our data supports the clinical testing of KSQ-4279 in combination with PARP inhibitors. Citation Format: Erica Tobin, Pamela Sullivan, Morgan Murray, Hugh Gannon, Anne Dodson, Sol Shenker, Frank Stegmeier, Andrew Wylie, Louise Cadzow. KSQ-4279, a first-in-class USP1 inhibitor shows strong combination activity with multiple PARP inhibitors in BRCA mutant cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1581.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2023-1581
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2023
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  • 5
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    Abstract ND01: KSQ-4279: A first-in-class USP1 inhibitor for the treatment of cancers with homologous recombination deficiencies
    American Association for Cancer Research (AACR) ; 2022
    In:  Cancer Research Vol. 82, No. 12_Supplement ( 2022-06-15), p. ND01-ND01
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 82, No. 12_Supplement ( 2022-06-15), p. ND01-ND01
    Abstract: Tumors with BRCA1/2 mutations and other homologous repair deficiencies (HRD) are vulnerable to agents that target the remaining DNA repair pathways, including platinum-containing chemotherapy agents and molecules targeting poly (ADP-ribose) polymerase-1 (PARP1). Despite the clinical benefit achieved with these drugs, many patients achieve incomplete disease control and resistance often emerges. With the goal of addressing this clinical need, we applied our proprietary CRISPRomics technology to identify novel targets in cancer indications characterized by defects in DNA repair pathways. One of the top ranked targets was the deubiquitinating enzyme USP1. USP1 has established roles in DNA damage repair processes including Translesion Synthesis and the Fanconi Anemia pathway. We developed KSQ-4279, a potent, highly selective inhibitor of USP1. KSQ-4279 was active in cells, leading to the accumulation of mono-ubiquitinated substrates of USP1 and inhibited the proliferation of cancer cell lines with BRCA mutations or other HRD alterations. Studies investigating the effect of combining KSQ-4279 with PARP inhibitors revealed clear evidence of synergy in cell lines with partial or no sensitivity to each agent alone. To investigate how the distinct mechanisms of action of KSQ-4279 and PARP inhibitors would be reflected in their resistance profiles, we used our CRISPRomics technology to perform functional genomic resistance screens. The top scoring resistance genes for KSQ-4279 were distinct from those identified for PARP inhibitors, which raised the possibility that combining PARP and USP1 inhibitors may provide more durable disease control by reducing the emergence of resistance. Evaluation of KSQ-4279 in patient-derived ovarian and triple-negative breast cancer xenograft models demonstrated dose-dependent tumor growth inhibition as a single agent and in combination with PARP inhibitors. In xenograft models that were insensitive or only partially sensitive to PARP inhibitors, the combination of KSQ-4279 and Olaparib led to tumor regressions and durable tumor control. This data supports the ongoing clinical trial of KSQ-4279 in patients with tumors harboring BRCA1/2 or other HRD mutations, both as a single agent and in combination with PARP inhibitors. Citation Format: Louise Cadzow, Erica Tobin, Pamela Sullivan, Sol Shenker, Sumeet Nayak, Janid Ali, Hugh Gannon, Anne Dodson, Paula Grasberger, Alyssa Carlson, Michael McGuire, Jehrod Brenneman, Hanlan Liu, Andrew Olaharski, Kerstin Sinkevicius, Jeff Hixon, Elsa Krall, Mike Schlabach, Matt Goulet, Jeremy Wilt, Patricia Harris, Frank Stegmeier, Andrew Wylie. KSQ-4279: A first-in-class USP1 inhibitor for the treatment of cancers with homologous recombination deficiencies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr ND01.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2022-ND01
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2022
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    Abstract 2771: KSQ-4279 mediated USP1 inhibition induces replication associated DNA gaps that contribute to cell death
    American Association for Cancer Research (AACR) ; 2023
    In:  Cancer Research Vol. 83, No. 7_Supplement ( 2023-04-04), p. 2771-2771
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 83, No. 7_Supplement ( 2023-04-04), p. 2771-2771
    Abstract: Tumors with defects in DNA double strand break (DSB) repair pathways, including those with mutations in BRCA1/2, are often treated with either poly (ADP-ribose) polymerase-1 (PARP1) inhibitors or platinum-based chemotherapy. Despite their clinical benefits, many patients develop resistance leading to the need for novel therapeutic approaches. To address this unmet clinical need, we applied our CRISPRomics® platform to identify novel therapeutic targets for DNA damage and repair deficient cancers. One of the top ranked targets was the deubiquitinating enzyme, USP1, with known functions in DNA damage repair pathways of translesion synthesis (TLS) and fanconi anemia (FA). We developed a novel small molecule inhibitor, KSQ-4279, that selectively inhibits USP1 and leads to accumulation of mono-ubiquitinated USP1 substrates such as proliferating nuclear antigen (PCNA). In addition to KSQ-4279’s activity in BRCA mutant tumors with known homologous recombination deficiencies (HRD), KSQ-4279 also exhibits synergistic activity in combination with PARP inhibitors and re-sensitizes PARP refractory tumors. Mechanistically, we show that in sensitive cell lines, treatment with KSQ-4279 alters the replication fork dynamics resulting in replication stress via induction of replication associated single stranded DNA gaps and subsequent fork degradation. Additionally, KSQ-4279 leads to loss of the essential DNA replication and repair protein, PCNA, which can be rescued by blocking PCNA ubiquitination either through Rad18 knockout or by ectopic expression of a PCNA K164R mutant. This loss of PCNA and sensitizing ssDNA lesions eventually lead to DNA double strand breaks (DSBs) and wide-spread DNA damage accumulation that contributes to cell death. This mechanistic insight supports the ongoing clinical trial of KSQ-4279 in patients with tumors harboring BRCA1/2 or other HRD mutations, both as a single agent and in combination with PARP inhibitors. Citation Format: Sumeet Nayak, Pamela Sullivan, Yuji Mishina, Anne Dodson, Pei-Lun Kao, Hugh Gannon, Chris Middleton, Sol Shenker, Morgan Murray, Michael Schlabach, Frank Stegmeier, Erica Tobin, Louise Cadzow, Andrew Wylie. KSQ-4279 mediated USP1 inhibition induces replication associated DNA gaps that contribute to cell death [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2771.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2023-2771
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2023
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    Abstract C101: Comprehensive identification of novel therapeutic targets for treatment of PD-1 resistant solid tumors via a genome-scale CRISPR/Cas9 in vivo T-cell screen
    American Association for Cancer Research (AACR) ; 2019
    In:  Molecular Cancer Therapeutics Vol. 18, No. 12_Supplement ( 2019-12-01), p. C101-C101
    Details
    In: Molecular Cancer Therapeutics, American Association for Cancer Research (AACR), Vol. 18, No. 12_Supplement ( 2019-12-01), p. C101-C101
    Abstract: Although immunotherapy with PD-1/PD-L1 antagonists has significantly advanced patient care, the majority of cancer patients currently do not benefit from checkpoint inhibitor therapies. To identify novel targets for the treatment of PD-1 insensitive cancers, we developed a novel Immune-CRISPRomicsTM platform that enabled genome-wide CRISPR/Cas9 screens in primary T cells in an in vivo setting. Notably, the screen identified clinically active molecules, such as PD-1 and also predicted recent clinical failures. In addition, we identified multiple targets that enhanced anti-tumor T-cell function similar to or better than PD-1 as a monotherapy. The anti-tumor activity of targets was assessed across a collection of PD-1 sensitive and PD-1 refractory syngeneic tumor models. One of the targets identified, IO-7, was found to possess robust activity across multiple PD-1 refractory models. We found that inhibition of IO-7 leads to long-term T-cell memory and prevents tumor growth upon re-challenge. Moreover, mechanistic follow-up studies demonstrate that IO-7 inhibition leads to an expansion of central memory T-cell subsets, which have been implicated in driving the durable clinical response of checkpoint inhibitors. We describe the first genome-wide in vivo T-cell CRISPR/Cas9 screen, which identified multiple therapeutic targets that present promising therapeutic opportunities for the treatment of PD-1 resistant solid tumors. Citation Format: Isabelle Le Mercier, Jason J. Merkin, Sean Keegan, Conor Calnan, Anja F. Hohmann, Nick Colletti, Eric Fagerberg, Sol Shenker, Caroline Bullock, Chris Wrocklage, Noah Tubo, Tianlei Xu, Matt Noyes, Rami Rahal, Sean Arlauckas, Aria Pearlman Morales, Frank Stegmeier, Louise Cadzow, Mike Schlabach, Gregory Kryukov, Micah J. Benson. Comprehensive identification of novel therapeutic targets for treatment of PD-1 resistant solid tumors via a genome-scale CRISPR/Cas9 in vivo T-cell screen [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr C101. doi:10.1158/1535-7163.TARG-19-C101
    Type of Medium: Online Resource
    ISSN: 1535-7163 , 1538-8514
    URL: Article
    DOI: 10.1158/1535-7163.TARG-19-C101
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2019
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    186 Development of KSQ-001, an engineered TIL (eTIL) therapy for solid tumors through CRISPR/Cas9-mediated editing of SOCS1
    BMJ ; 2021
    In:  Journal for ImmunoTherapy of Cancer Vol. 9, No. Suppl 2 ( 2021-11), p. A198-A198
    Details
    In: Journal for ImmunoTherapy of Cancer, BMJ, Vol. 9, No. Suppl 2 ( 2021-11), p. A198-A198
    Abstract: Adoptive cell therapy with ex vivo expanded tumor infiltrating lymphocytes (TIL) offers a potentially curative treatment for cancer. However, the immunosuppressive tumor microenvironment limits the effectiveness of TIL therapy. To address this medical need, we used our Immune-CRISPRomics® Platform to perform a series of genome-wide CRISPR/Cas9 screens to identify targets enhancing the ability of T cells to infiltrate and kill solid tumors in an in vivo setting. These screens identified SOCS1 as a top target that restrains T cell anti-tumor immunity. Based on these findings, we developed KSQ-001, an engineered TIL (eTIL) therapy created via CRISPR/Cas9-mediated editing of SOCS1 for the treatment of solid tumors. Methods Genome-wide CRISPR/Cas9 screens were conducted in in vitro primary human T cells and TIL cultures and in in vivo primary mouse OT1 and PMEL-TCR-Tg T cells in syngeneic tumor models. The efficacy of surrogate murine KSQ-001 (mKSQ-001), in which the SOCS1 gene is inactivated by CRISPR/Cas9 in OT1 or PMEL-TCR-Tg T cells, was evaluated in both the B16-Ova and CRC-gp100 syngeneic tumor models, with memory formation and efficacy evaluated both in the presence and absence of cyclophosphamide-mediated lymphodepletion. KSQ-001 was manufactured from human TIL using SOCS1-targeting sgRNAs selected for therapeutic use based on potency and selectivity, with KSQ-001 characterized for in vitro function and in vivo anti-tumor efficacy. Results Upon adoptive transfer of a single dose into solid tumor-bearing hosts, mKSQ-001 was found to robustly enhance anti-tumor efficacy and eradicate tumors in 7/10 mice in the PD1-sensitive OT1/B16-Ova model and to drive responses in the PD-1 refractory PMEL/CRC-gp100 syngeneic tumor model. mKSQ-001 also showed a ten-fold increase in anti-tumor potency in vivo compared to unengineered T-cell product and established durable anti-tumor memory by persisting in the form of T central memory cells detectable at high frequency in the peripheral blood of complete responder mice. In the setting of lymphodepletion, mKSQ-001 also displayed heightened anti-tumor potency, accumulation, and memory formation in comparison to inactivation of PD-1. Importantly, human KSQ-001 displayed a transcriptional signature indicative of increased anti-tumor function, produced increased amounts of pro-inflammatory cytokines, exhibited a hypersensitivity to IL-12 signaling, and demonstrated increased anti-tumor function both in vitro and in vivo solid tumor models. Conclusions Based on insights from our Immune-CRISPRomics® platform and demonstrated efficacy across multiple preclinical tumor models, we have developed KSQ-001, a novel eTIL therapy. These preclinical data support clinical testing of KSQ-001 in a variety of solid tumor indications.
    Type of Medium: Online Resource
    ISSN: 2051-1426
    URL: Article
    DOI: 10.1136/jitc-2021-SITC2021.186
    Language: English
    Publisher: BMJ
    Publication Date: 2021
    detail.hit.zdb_id: 2719863-7
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