scholarly journals 959 Safety and anti-tumor activity of TCR-engineered autologous, PRAME-directed T cells across multiple advanced solid cancers at low doses – clinical update on the ACTengine® IMA203 trial

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A1009-A1009
Author(s):  
Martin Wermke ◽  
Apostolia-Maria Tsimberidou ◽  
Ali Mohamed ◽  
Andrea Mayer-Mokler ◽  
Arun Satelli ◽  
...  
Keyword(s):  
T Cells ◽  
Cancer Patients ◽  
Adoptive Cell Therapy ◽  
Primary Objective ◽  
Immunological Methods ◽  
Solid Cancer ◽  
Median Dose ◽  
Human Dose ◽  
Dose Levels ◽  
Anti Tumor Activity

BackgroundAdoptive cell therapy demonstrated significant clinical benefit in patients with hematological malignancies but results in most solid tumors have been less encouraging so far.In the IMA203 trial we are treating advanced solid cancer patients utilizing TCR-engineered T cells (TCR-T) directed against an HLA-A*02-restricted peptide derived from the highly prevalent cancer testis antigen PRAME. This target was selected due to homogenous expression and exceptionally high target peptide density per tumor cell (assessed by quantitative mass spectrometry), two features we hypothesize to be critical determinants of anti-tumor activity in TCR-T trials.MethodsThis ongoing first-in-human, dose escalation, multi-indication trial enrolls HLA-A*02:01- and PRAME-positive recurrent and/or refractory solid cancer patients, who failed all available standard treatments. Eligible patients undergo leukapheresis and an autologous TCR-T product is manufactured. After lymphodepletion with fludarabine and cyclophosphamide, T cells are infused, followed by low-dose IL-2. The primary objective of the trial is to assess the safety and tolerability of IMA203. Secondary objectives are to evaluate the anti-tumor activity and pharmacodynamics using molecular and immunological methods.ResultsAs of August 15, 2021, 16 heavily pre-treated patients received IMA203 T cells across multiple escalating dose levels (DL). Absolute IMA203 doses infused ranged from 0.08 to 0.81x109 transduced CD8 T cells per patient, which to our knowledge did not lead to anti-tumor responses in other TCR-T trials. Treatment-emergent adverse events after IMA203 infusion were transient and manageable. Most common events were expected cytopenias (G1-4), CRS and ICANS (both G1-2) and 1 DLT in DL2 (reported earlier). All evaluable patients (N=12) achieved disease control (i.e. best overall response: stable disease [SD] or partial response [PR]) and 6 patients demonstrated PRs according to RECIST1.1 with 2 of these PRs being confirmed. While all 3 patients treated at DL1 (median dose: 0.11x109) experienced SD, a PR was observed in 6/9 patients treated beyond DL1 (median dose: 0.30x109). Responses were seen in patients with synovial sarcoma (N=3), malignant melanoma (N=2) and head and neck cancer (N=1). Robust engraftment of T cells was observed in all patients and tumor infiltration by TCR-modified T cells was demonstrated in patients with evaluable on-treatment biopsies.ConclusionsTo our knowledge IMA203 is the first TCR-T product candidate that induced frequent tumor responses across multiple solid cancers using transduced T cells at doses below 1 billion and has a manageable safety profile. The next step is to assess response rates at higher dose levels and durability of responses.Trial RegistrationNCT03686124Ethics ApprovalThe study was approved by the institutional review board/ethics committee as required for each participating site.

scholarly journals Innate Immune Cells and Their Contribution to T-Cell-Based Immunotherapy

2020 ◽  
Vol 21 (12) ◽  
pp. 4441 ◽  
Author(s):  
Pierpaolo Ginefra ◽  
Girieca Lorusso ◽  
Nicola Vannini
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cancer Immunotherapy ◽  
Cancer Patients ◽  
Immune Cells ◽  
Adoptive Cell Therapy ◽  
Adaptive Immune Response ◽  
Immune Checkpoint Blockade ◽  
Innate Immune ◽  
Innate Immune Cells

In recent years, immunotherapy has become the most promising therapy for a variety of cancer types. The development of immune checkpoint blockade (ICB) therapies, the adoptive transfer of tumor-specific T cells (adoptive cell therapy (ACT)) or the generation of T cells engineered with chimeric antigen receptors (CAR) have been successfully applied to elicit durable immunological responses in cancer patients. However, not all the patients respond to these therapies, leaving a consistent gap of therapeutic improvement that still needs to be filled. The innate immune components of the tumor microenvironment play a pivotal role in the activation and modulation of the adaptive immune response against the tumor. Indeed, several efforts are made to develop strategies aimed to harness innate immune cells in the context of cancer immunotherapy. In this review, we describe the contribution of innate immune cells in T-cell-based cancer immunotherapy and the therapeutic approaches implemented to broaden the efficacy of these therapies in cancer patients.

scholarly journals Clinical-scale selection and viral transduction of human naïve and central memory CD8+ T cells for adoptive cell therapy of cancer patients

2013 ◽  
Vol 62 (10) ◽  
pp. 1563-1573 ◽  
Author(s):  
Anna Casati ◽  
Azam Varghaei-Nahvi ◽  
Steven Alexander Feldman ◽  
Mario Assenmacher ◽  
Steven Aaron Rosenberg ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Therapy ◽  
Cancer Patients ◽  
Cd8 T Cells ◽  
Adoptive Cell Therapy ◽  
Central Memory ◽  
Clinical Scale ◽  
Scale Selection ◽  
Memory Cd8 T Cells ◽  
Viral Transduction

scholarly journals In the Absence of a TCR Signal IL-2/IL-12/18-Stimulated γδ T Cells Demonstrate Potent Anti-Tumoral Function Through Direct Killing and Senescence Induction in Cancer Cells

Cancers ◽  
2020 ◽  
Vol 12 (1) ◽  
pp. 130 ◽  
Author(s):  
Karin Schilbach ◽  
Christian Welker ◽  
Naomi Krickeberg ◽  
Carlotta Kaißer ◽  
Sabine Schleicher ◽  
...  
Keyword(s):  
T Cells ◽  
Cancer Cells ◽  
Adoptive Cell Therapy ◽  
Γδ T Cells ◽  
Cell Receptor ◽  
Tcr Signaling ◽  
Tumor Recognition ◽  
Ifn Γ ◽  
The Impact ◽  
Anti Tumor Activity

Abundant IFN-γ secretion, potent cytotoxicity, and major histocompatibility complex-independent targeting of a large spectrum of tumors make γδ T cells attractive candidates for cancer immunotherapy. Upon tumor recognition through the T-cell receptor (TCR), NK-receptors, or NKG2D, γδ T cells generate the pro-inflammatory cytokines TNF-α and IFN-γ, or granzymes and perforin that mediate cellular apoptosis. Despite these favorable potentials, most clinical trials testing the adoptive transfer of pharmacologically TCR-targeted and expanded γδ T cells resulted in a limited response. Recently, the TCR-independent activation of γδ T cells was identified. However, the modulation of γδ T cell’s effector functions solely by cytokines remains to be elucidated. In the present study, we systematically analyzed the impact of IL-2, IL-12, and IL-18 in parallel with TCR stimulation on proliferation, cytokine production, and anti-tumor activity of γδ T cells. Our results demonstrate that IL-12 and IL-18, when combined, constitute the most potent stimulus to enhance anti-tumor activity and induce proliferation and IFN-γ production by γδ T cells in the absence of TCR signaling. Intriguingly, stimulation with IL-12 and IL-18 without TCR stimulus induces a comparable degree of anti-tumor activity in γδ T cells to TCR crosslinking by killing tumor cells and driving cancer cells into senescence. These findings approve the use of IL-12/IL-18-stimulated γδ T cells for adoptive cell therapy to boost anti-tumor activity by γδ T cells.

Immunomodulation by HDAC inhibition: Results from a phase I study with entinostat in combination with atezolizumab and bevacizumab in metastatic renal cell carcinoma patients.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 5064-5064
Author(s):  
Roberto Pili ◽  
Nabil Adra ◽  
Nur Damayanti ◽  
Theodore F. Logan ◽  
Vivek Narayan ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
T Cells ◽  
Phase I ◽  
Cell Carcinoma ◽  
Phase Ii ◽  
Renal Cell ◽  
Phase I Study ◽  
Checkpoint Inhibitors ◽  
Primary Objective ◽  
Dose Levels

5064 Background: Immunosuppressive regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs) limit the efficacy of immunotherapies. We have previously reported that the HDAC inhibitor entinostat has synergistic antitumor effect in combination with immunotherapies in preclinical models by inhibiting Tregs and MDSCs function. The combination of atezolizumab (PD-L1 inhibitor) and bevacizumab (VEGF inhibitor) is active in renal cell carcinoma (RCC). Thus, we have conducted a Phase I study with entinostat, atezolizumab and bevacizumab in patients (pts) with metastatic RCC. Methods: The primary objective was to evaluate safety and tolerability. The phase I portion included 3 dose levels of entinostat (1 mg, 3 mg or 5 mg, PO weekly) and fixed, standard doses of atezolizumab (1200 mg IV every 21 days) and bevacizumab (15 mg/Kg IV every 21 days). Pts with any histological type and prior therapies were included. Results: Dose levels were completed with up to 1 DLT/dose level. 5 mg was the Phase II recommended dose for entinostat. DLTs included hypertension, encephalopathy, hyponatremia and pruritus. The most common resolved grade 3/4 toxicities were hypophosphatemia (33%), hypertension (17%), and pneumonitis (11%). We have enrolled 18 pts (17 evaluable for ORR by RECIST). 5 pts continue on treatment. 3 pts discontinued treatment because of adverse events, 9 pts for disease progression, and one pt for physician decision. Good risk and intermediate risk pts were 61% and 39%, respectively. Overall ORR was 47.1% (95% CI 23.0-72.2) and median PFS was 7.6 months (95% CI 1.6-16.3). In pts with no prior therapies (12) the ORR was 58.3% (95% CI 27.7-84.8) and median PFS was 13.4 months (95% CI 1.5-28.9). One additional PR was observed by ir-RC but was not confirmed within the data cut-off date of 11/11/19. In pts with prior immune checkpoint inhibitors (ICIs) (5) ORR was 20% (95% CI 0.5-71.6) and median PFS was 7.6 months (95% CI 1.3-NR). Preliminary data show a statistically significant lower % of circulating monocytic MDSC (HLADR−1CD11b+CD33highCD14+CD15−) and exhausted T cells (CD45+CD3+CD8+TIM3+) following treatment in pts (4) with objective responses as compared to pts (4) with progressive disease. Conclusions: The results from this phase I suggest that the combination of entinostat, atezolizumab and bevacizumab is relatively well tolerated and is active in renal cell carcinoma patients, in both ICIs naïve and resistant disease. A phase II portion of this study is currently accruing patients. Clinical trial information: NCT03024437 .

scholarly journals Tumor-targeted T cells modified to secrete IL-12 eradicate systemic tumors without need for prior conditioning

Blood ◽  
2012 ◽  
Vol 119 (18) ◽  
pp. 4133-4141 ◽  
Author(s):  
Hollie J. Pegram ◽  
James C. Lee ◽  
Erik G. Hayman ◽  
Gavin H. Imperato ◽  
Thomas F. Tedder ◽  
...  
Keyword(s):  
T Cells ◽  
Cancer Patients ◽  
Adoptive Cell Therapy ◽  
Tumor Model ◽  
T Cell Subsets ◽  
T Regulatory Cell ◽  
Intrinsic Resistance ◽  
Adoptive Therapy ◽  
Established Disease ◽  
Conditioning Regimens

Abstract Adoptive cell therapy with tumor-targeted T cells is a promising approach to cancer therapy. Enhanced clinical outcome using this approach requires conditioning regimens with total body irradiation, lymphodepleting chemotherapy, and/or additional cytokine support. However, the need for prior conditioning precludes optimal application of this approach to a significant number of cancer patients intolerant to these regimens. Herein, we present preclinical studies demonstrating that treatment with CD19-specific, chimeric antigen receptor (CAR)–modified T cells that are further modified to constitutively secrete IL-12 are able to safely eradicate established disease in the absence of prior conditioning. We demonstrate in a novel syngeneic tumor model that tumor elimination requires both CD4+ and CD8+ T-cell subsets, autocrine IL-12 stimulation, and subsequent IFNγ secretion by the CAR+ T cells. Importantly, IL-12–secreting, tumor-targeted T cells acquire intrinsic resistance to T regulatory cell–mediated inhibition. Based on these preclinical data, we anticipate that adoptive therapy using CAR-targeted T cells modified to secrete IL-12 will obviate or reduce the need for potentially hazardous conditioning regimens to achieve optimal antitumor responses in cancer patients.

Immunotherapy with Chimeric Antigen Receptor Targeting Intracellular WT1 Gene Product Complexed with HLA-a*24:02 Molecule

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4292-4292 ◽  
Author(s):  
Hiroaki Ikeda ◽  
Yasushi Akahori ◽  
Motohiro Yoneyama ◽  
Yuki Orito ◽  
Yoshihiro Miyahara ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Therapy ◽  
B Cell ◽  
Cancer Patients ◽  
Chimeric Antigen Receptor ◽  
Potential Risk ◽  
Research Funding ◽  
Adoptive Cell Therapy ◽  
Antigen Receptor ◽  
Epitope Peptide

Abstract Adoptive cell therapy with lymphocytes transduced with chimeric antigen receptor (CAR) is a promising strategy to treat cancer patients. Recent success in the treatment of patients with B cell malignancy by CD19-CAR encourages the development of successive CAR therapy targeting other tumor-associated antigens. However, the search for the appropriate target molecule for CAR, other than B cell markers, is a serious question. The target of CAR is generally limited to the cellular surface molecules, making difficult to expand CAR therapy for broad range of cancer patients. Inspired by the physiological recognition of epitope peptide and MHC molecule (pMHC) by T cells, we have generated a series of antibodies that recognize the pMHC complexes with peptides derived from tumor antigens expressed intracellularly. We isolated an scFv antibody clone WT#213 that can specifically recognize WT1 p235-243 peptide (CMTWNQMNL) complexed with HLA-A*24:02 molecule by the screening of human antibody scFv phage display library. We have constructed retrovirus that encodes the CAR consists of WT#213 and intracellular signal transduction domains of CD3z and GITR (WT#213 CAR). We confirmed the specific recognition of endogenous WT1-expressing cells by the CAR-T cells with the intracellular cytokine staining and the 51Cr release cytotoxic assay. Utilizing NOG immunodeficient mice, we demonstrated the effectiveness of adoptive cell therapy with WT#213 CAR against the WT1 expressing HLA-A*24:02 positive human leukemia cells. To evaluate the safety of the WT#213 CAR, we predicted the potential property of WT#213 CAR to cross-react to normal tissues in humans. We conducted alanine scan analysis of WT1p235-243 peptide that was recognized by WT#213 CAR as well as the TCR derived from CTL clone TAK-1 which recognizes same epitope peptide in association with HLA-A*24:02 to define the amino acids that were critically important in the recognition by the WT#213 CAR or TAK-1-derived TCR. After BLAST search, we synthesized the normal protein-derived peptides with potential risk of cross-reactivity, and tested the recognition of these peptides by WT#213 CAR or TAK-1-derived TCR. Although the critical peptides, and therefore the peptides with potential risk, were quite different between the WT#213 CAR and TAK-1-derived TCR, none of these peptides showed the stimulation of WT#213 CAR or TAK-1-derived TCR. The results here suggest that the immunotherapy with WT#213 CAR will be effective for the treatment of the leukemia patients without the predicted risk at least in the evaluation we performed. Figure 1. Figure 1. Disclosures Ikeda: Takara Bio Inc.: Research Funding. Akahori:Takara Bio Inc.: Research Funding. Miyahara:Takara Bio Inc.: Research Funding. Amaishi:Takaa Bio Inc.: Employment. Okamoto:Takara Bio Inc.: Employment. Mineno:Takara Bio Inc.: Employment. Takesako:TAKARA BIO INC.: Employment. Fujiwara:Celgene: Honoraria, Other: Travel, Acomodations, Expenses.

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