KITE-439: A phase I study of HPV16 E7 T cell receptor-engineered T cells in patients with relapsed/refractory HPV16-positive cancers.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. TPS3149-TPS3149
Author(s):  
Kedar Kirtane ◽  
Erminia Massarelli ◽  
Glenn J. Hanna ◽  
Christopher Austin Klebanoff ◽  
George Blumenschein ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
T Cells ◽  
T Cell ◽  
Head And Neck ◽  
Tumor Cells ◽  
T Cell Receptor ◽  
Primary Endpoint ◽  
Cell Receptor ◽  
Engineered T Cells ◽  
Phase 1B

TPS3149 Background: Human papillomavirus 16 (HPV16) is the most prominent subtype across invasive head and neck cancers, as well as cervical cancer and other anogenital cancers (Saraiya M, et al. J Natl Cancer Inst. 2015). The HPV16 E7 (E7) viral antigen is important for the survival of HPV-positive tumor cells but is absent from normal human tissue, making it an attractive target for anti-cancer therapy. Preclinical efficacy has been observed with MHC class I-restricted T cell receptor (TCR)-engineered T cells targeting E7 on HPV16-positive tumor cells (Jin BY, et al. JCI Insight. 2018). This Phase 1, first-in-human, open-label, multicenter study (NCT03912831) will evaluate the safety and efficacy of KITE-439, an autologous TCR-engineered T cell therapy targeting E7, in HLA-A*02:01–positive patients with relapsed/refractory HPV16-positive cancers. Methods: A single-patient dose-escalation schema will be used in Phase 1A of the study, enrolling up to 30 patients. Phase 1A will evaluate safety and inform the recommended dose of KITE-439 for Phase 1B. Approximately 45 patients with squamous cell cancer of the head and neck, cervical cancer, and other HPV16-positive tumors will be included in Phase 1B. Patients in Phase 1A and Phase 1B may receive optional bridging therapy followed by cyclophosphamide and fludarabine conditioning chemotherapy. Patients will then receive an infusion of KITE-439 at 1 × 106 up to 1 × 108 TCR-transduced T cells/kg along with daily subcutaneous IL-2 therapy for a maximum of 14 doses post-infusion. The primary endpoint for Phase 1A is the incidence of adverse events defined as dose-limiting toxicities. The primary endpoint for Phase 1B is investigator-assessed objective response rate per modified RECIST v1.1 criteria (Eisenhauer EA, et al. Eur J Cancer. 2009). Secondary endpoints for Phase 1B include duration of response, progression-free survival, overall survival, and safety. Patients ≥ 18 years must be HLA-A*02:01–positive and have relapsed/refractory HPV16-positive cancer, an ECOG PS of ≤ 1, and adequate bone marrow and organ function. Key exclusion criteria include a history of stroke, myocardial infarction, or symptomatic deep vein thrombosis/pulmonary embolism, known infection with human immunodeficiency virus, detectable hepatitis C, or detectable hepatitis B. This study is currently open and accruing patients. Clinical trial information: NCT03912831 .

Identification of HLA-A0201 restricted epitope of novel cancer/testis antigens VCX/Y and generation of antigen-specific T-cell receptor engineered T cells for treatment of solid tumor malignancies.

2018 ◽  
Vol 36 (5_suppl) ◽  
pp. 160-160
Author(s):  
Ke Pan ◽  
Cassian Yee
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Therapy ◽  
High Activity ◽  
Tumor Cells ◽  
T Cell Receptor ◽  
Cell Receptor ◽  
Engineered T Cells ◽  
Restricted Epitope ◽  
Cancer Testis

160 Background: To identify HLA-A0201 restricted epitope of novel cancer/testis antigen VCX/Y, generate antigen specific T cells and T-cell receptor (TCR) engineered T cells for adoptive cell therapy (ACT) of solid cancer patients. Methods: Reverse-immunology method was used to identify HLA-A0201 restricted epitope of VCX/Y. The high binding score peptide or whole length of VCX3A mRNA were pulsed or transfected to mature dendritic cells (mDC) from HLA-A0201+ donor and then stimulated autologous naïve T cells. Tetramer guided sorting were performed to purify the epitope specific T cells and CTL clones were generated with limiting dilution. TCR were cloned out from high activity CTL clone and the recombinant of retrovirus vector were constructed to introduce the TCR to allogeneic PBMC to generate the TCR engineered T cells. Results: One peptide which its sequence was shared with all VCX/Y members was identified. Interesting, only CTL clone generated from simulation of VCX3A mRNA transfected DC can recognize naturally processed VCX/Y presented by HLA-A0201+ tumor cells. Cold target inhibition detection confirmed that this VCX/Y peptide was naturally processed and recognized by HLA-A0201+ CTL clone. After infection of retrovirus containing the TCR from high activity of CTL clone, the TCR engineered T cells can recognize HLA-A2+ tumor cells but not normal lung cells. Moreover, these TCR engineered T cells specifically secreted IFN-γ in response to T2 cells pulsed with peptide, as well as HLA-A0201+ and VCX/Y overexpressed tumor cells. Conclusions: VCX/Y peptide we identified is a novel candidate peptide antigen for vaccine or for endogenous adoptive T cell therapy. The correlated high activity TCR gene can generate TCR engineered T cells from patients with anti-tumor activity and offer an alternative adoptive T cell treatment for patients with VCX/Y expressing solid tumor malignancies.

Screening of neoantigen-specific T cells and establishment of T-cell receptor-engineered T cells: Implications for head and neck squamous carcinoma.

2018 ◽  
Vol 36 (15_suppl) ◽  
pp. 3048-3048
Author(s):  
Lili Ren ◽  
Tatsuo Matsuda ◽  
Boya Deng ◽  
Kazuma Kiyotani ◽  
Taigo Kato ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Head And Neck ◽  
T Cell Receptor ◽  
Squamous Carcinoma ◽  
Cell Receptor ◽  
Engineered T Cells

scholarly journals Effective screening of T cells recognizing neoantigens and construction of T-cell receptor-engineered T cells

Oncotarget ◽  
2018 ◽  
Vol 9 (13) ◽  
pp. 11009-11019 ◽  
Author(s):  
Taigo Kato ◽  
Tatsuo Matsuda ◽  
Yuji Ikeda ◽  
Jae-Hyun Park ◽  
Matthias Leisegang ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Cell Receptor ◽  
Effective Screening ◽  
Engineered T Cells

Abstract 625: Eradication of cancer cells by T-cell receptor-engineered T cells targeting neoantigens/oncoantigens

2017 ◽  
Author(s):  
Tatsuo Matsuda ◽  
Taigo Kato ◽  
Yuji Ikeda ◽  
Matthias Leisegang ◽  
Sachiko Yoshimura ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cancer Cells ◽  
T Cell Receptor ◽  
Cell Receptor ◽  
Engineered T Cells

scholarly journals The Anticancer Potential of T Cell Receptor-Engineered T Cells

2021 ◽  
Vol 7 (1) ◽  
pp. 48-56
Author(s):  
Matyas Ecsedi ◽  
Megan S. McAfee ◽  
Aude G. Chapuis
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Cell Receptor ◽  
Engineered T Cells

scholarly journals Regression of Epithelial Cancers Following T Cell Receptor Gene Therapy Targeting Human Papillomavirus-16 E7

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 492-492 ◽  
Author(s):  
Scott Michael Norberg ◽  
Nisha Nagarsheth ◽  
Stacey Doran ◽  
Jennifer A Kanakry ◽  
Sabina Adhikary ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Conditioning Regimen ◽  
Cell Receptor ◽  
Epithelial Cancer ◽  
Hpv 16 ◽  
Epithelial Cancers ◽  
Anti Cancer ◽  
Engineered T Cells

Abstract Background: Adoptive T cell therapy with gene-engineered T cells is an emerging cancer treatment strategy that has been applied successfully to the treatment of hematological cancers. We conducted a clinical trial to test proof of principle for this type of treatment in an epithelial cancer. Patients with human papillomavirus (HPV) 16-associated cancers were treated with gene-engineered T cells targeting HPV16 E7. Methods: The clinical trial was a phase I study with a 3 + 3 design and three dose levels (DL) of gene-engineered T cells (DL1: 1 x 109, DL2: 1 x 1010, DL3: 1 x 1011). Patients had metastatic HPV-16+ cancers from any primary tumor site. Treatment consisted of a one-time infusion of autologous T cells that were gene-engineered to express an HLA-A*02:01-restricted T-cell receptor (TCR) that targets HPV-16 E7 (E7 T cells). A lymphocyte-depleting conditioning regimen was administered before treatment. E7 T cell infusion was followed by high-dose systemic aldesleukin. Results: Twelve patients were treated (DL1, n=3; DL2, n=3; DL3, n=6). The age range was 31 to 59 years. The site of the primary cancer was vulva (n=1), head and neck (n=4), uterine cervix (n=5), and anus (n=2). Each patient had multiple metastases and had previously received 3 to 7 anti-cancer agents. The conditioning regimen consisted of cyclophosphamide 30 mg/Kg (n=6) or 60 mg/Kg (n=6) iv daily for 2 days overlapping with fludarabine 25 mg/m2 iv daily for 5 days. The E7 TCR was expressed by 90-99% of the infused T cells for each patient. E7 T cell cross-reactivity against healthy tissues was not identified. Cytokine-release syndrome was not observed. A single patient, at DL3, experience dose-limiting toxicity. Four patients experienced confirmed responses, and two patients experienced unconfirmed responses (i.e. met criteria for response at only one assessment) (Figure 1). Confirmed responses occurred in patients with cervical cancer, oropharyngeal cancer, vulvar cancer, and anal cancer. The duration of responses was 3 months (ongoing), 4 months, 8 months, and 9 months, respectively. These patients had previously received 7, 4, 7 and 3 prior anti-cancer agents, respectively. Three patients with confirmed responses had previously received PD-1 or PD-L1 checkpoint blockade. Four patients whose cancer progressed after E7 T cells received PD-1 or PD-L1 checkpoint blockade; none responded. Conclusions: Tumor regression can occur following treatment of an epithelial cancer with gene-engineered T cells. These findings support continued study of E7 T cells and possibly other types of gene-engineered T cells in epithelial cancers. Disclosures Adhikary: Kite Pharma: Employment. Schweitzer:Kite Pharma: Employment. Astrow:Kite Pharma: Employment. Hinrichs:Kite Pharma: Research Funding; NIH: Patents & Royalties: NIH patents related to cell therapy.

scholarly journals T Cells Engineered with a Novel Chimeric Receptor Demonstrate Durable In Vivo Efficacy Against Disseminated Multiple Myeloma

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 962-962 ◽  
Author(s):  
Ksenia Bezverbnaya ◽  
Vivian Lau ◽  
Craig Aarts ◽  
Galina Denisova ◽  
Arya Afsahi ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Cell Receptor ◽  
Inhibitory Effect ◽  
In Vivo Efficacy ◽  
Engineered T Cells

Abstract Despite recent therapeutic developments, multiple myeloma remains an incurable plasma cell malignancy. Poor prognosis for myeloma patients relapsing post-transplant calls for the need for novel treatment options. Immunotherapy with engineered T cells has proven highly efficacious against B-cell cancers, and early-phase clinical trials suggest that multiple myeloma is susceptible to this form of therapy. We designed a new chimeric T cell receptor, T cell antigen coupler (TAC), which relies upon activation through endogenous T cell receptor complex, thus allowing engineered T cells to auto-regulate their activity (Helsen et al, Nat. Comm., 2018). Using published single-chain antibody fragments (scFvs) C11D5.3 and J22.9-xi, we generated B cell maturation antigen (BCMA)-specific TAC receptors for targeting multiple myeloma. Primary human T cells were transduced with lentiviral vectors carrying different BCMA TAC constructs and assessed for in vitro functionality via cytokine production, cytotoxicity, and proliferation assays. In vivo efficacy and T cell tracking were performed in an established orthotopic xenograft mouse model based on a BCMA-positive KMS-11 cell line. C11D5.3 and J22.9-xi TAC T cells demonstrated comparable in vitro performance with both types of cultures efficiently killing BCMA-expressing targets, producing IFN-γ, TNF-α, and IL-2 cytokines, and undergoing multiple rounds of proliferation. In vivo, TAC T cells carrying either scFv were capable of curing mice bearing disseminated myeloma; however, the TAC T cells carrying J22.9-xi scFv were more potent on a per-cell basis (Figure 1A, top panel). Mice in remission 3 months post-treatment with a single dose of 106 TAC-positive T cells showed evidence of sustained anti-tumor protection upon rechallenge with a fresh dose of 106 KMS-11 tumor cells (Figure 1B). Mice treated with low-dose J22.9-xi T cells were more resistant to rechallenge than mice treated with a comparable dose of C11D5.3 TAC T cells. Tracking of the TAC T cells in vivo revealed that the J22.9-xi TAC T cells expanded to a much larger extent than the C11D5.3 TAC T cells (Figure 1A, bottom panel), indicating that there were likely more J22.9-xi TAC T cells present at the time of tumor rechallenge. To understand whether biological aspects of BCMA may influence the proliferative response of the TAC T cells, we explored the influence of APRIL, the soluble ligand for BCMA, on TAC T cell proliferation in vitro. Strikingly, despite comparable proliferation of both TAC T cell populations following stimulation with KMS-11 tumor cells in the absence of APRIL in vitro, the presence of APRIL had a strong inhibitory effect on proliferation of C11D5.3 TAC T cells and only a modest inhibitory effect on J22.9-xi TAC T cells. Our preclinical findings support further development of TAC T cells for the treatment of multiple myeloma and underscore the importance of T cell expansion in determining the therapeutic activity of engineered T cells. This work further reveals a novel observation that the natural ligand of BCMA can impair the therapeutic impact of T cells engineered with chimeric receptors directed against BCMA and provide a basis for advancing BCMA-specific TAC T cells into the clinic. Disclosures Denisova: Triumvira Immunologics: Patents & Royalties. Afsahi:Triumvira Immunologics: Patents & Royalties. Helsen:Triumvira Immunologics: Employment, Patents & Royalties. Bramson:Triumvira Immunologics: Employment, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding.

Combination of metabolic intervention and T cell therapy enhances solid tumor immunotherapy

2020 ◽  
Vol 12 (571) ◽  
pp. eaaz6667
Author(s):  
Meixi Hao ◽  
Siyuan Hou ◽  
Weishuo Li ◽  
Kaiming Li ◽  
Lingjing Xue ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Surface ◽  
Cell Therapy ◽  
Solid Tumors ◽  
T Cell Receptor ◽  
Chimeric Antigen Receptor ◽  
Cell Receptor ◽  
T Cell Therapy ◽  
Engineered T Cells

Treatment of solid tumors with T cell therapy has yielded limited therapeutic benefits to date. Although T cell therapy in combination with proinflammatory cytokines or immune checkpoints inhibitors has demonstrated preclinical and clinical successes in a subset of solid tumors, unsatisfactory results and severe toxicities necessitate the development of effective and safe combinatorial strategies. Here, the liposomal avasimibe (a metabolism-modulating drug) was clicked onto the T cell surface by lipid insertion without disturbing the physiological functions of the T cell. Avasimibe could be restrained on the T cell surface during circulation and extravasation and locally released to increase the concentration of cholesterol in the T cell membrane, which induced rapid T cell receptor clustering and sustained T cell activation. Treatment with surface anchor-engineered T cells, including mouse T cell receptor transgenic CD8+ T cells or human chimeric antigen receptor T cells, resulted in superior antitumor efficacy in mouse models of melanoma and glioblastoma. Glioblastoma was completely eradicated in three of the five mice receiving surface anchor-engineered chimeric antigen receptor T cells, whereas mice in other treatment groups survived no more than 64 days. Moreover, the administration of engineered T cells showed no obvious systemic side effects. These cell-surface anchor-engineered T cells hold translational potential because of their simple generation and their safety profile.

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