735MO Updated safety and efficacy from SURPASS, the phase I trial of ADP-A2M4CD8, a next-generation autologous T-cell receptor T-cell therapy, in previously treated patients with unresectable or metastatic tumors

Hong, D.S.; Asch, Adam S.; Calvo, Emiliano; Zugazagoitia, Jon; Charlson, John A.; Butler, Marcus O.; Moreno, Víctor; Tine, Brian Andrew Van; Lawrence, Donald P.; Johnson, Melissa L.; Lin, Q.; Annareddy, T.; Brophy, F.; Broad, Robyn; Soria, A. Derrac; Navenot, J-M.; Saro, Jose; Norry, E.; Clarke, Jeffrey

doi:10.1016/j.annonc.2022.07.861

Cited by 4 publications

(4 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…By comparison, only 8 out of the 37 TCRs that were selected for cell product manufacture in our neoTCR clinical trial had IFNγ EC 50 values below 10 ng ml -1 . As we learned from our own data about neoTCR T cell trafficking into the tumour and as more clinical data became available 42,43 , we narrowed the TCR affinity criteria for product selection in favour of higher affinity TCRs. These criteria were applied to the last two patients (0417 and 1003) who received the treatment in the current clinical trial.…”

Section: Discussionmentioning

confidence: 99%

“…The dose-escalation study started with cell doses that may be lower than would be needed for the potential of a clinical response, especially if we consider that the total transgenic cell dose was divided by the three TCRs in many patients. In the solid tumour setting, TCR transgenic T cell clinical trials conducted by other groups have shown clinical activity in the 5-10 × 10 9 per TCR range, with no clear dose response beyond 10 billion cells per TCR 42,43 . The improvements in the manufacturing process during the conduct of the trial and progressing through the cell doses led to better in vivo expansion in the last patients who received treatment, getting closer to the levels that would be therapeutic in other studies [21][22][23][24][25][26][27] .…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Non-viral precision T cell receptor replacement for personalized cell therapy

Foy¹,

Jacoby²,

Bota

et al. 2022

Nature

133

108

View full text Add to dashboard Cite

T cell receptors (TCRs) enable T cells to specifically recognize mutations in cancer cells1–3. Here we developed a clinical-grade approach based on CRISPR–Cas9 non-viral precision genome-editing to simultaneously knockout the two endogenous TCR genes TRAC (which encodes TCRα) and TRBC (which encodes TCRβ). We also inserted into the TRAC locus two chains of a neoantigen-specific TCR (neoTCR) isolated from circulating T cells of patients. The neoTCRs were isolated using a personalized library of soluble predicted neoantigen–HLA capture reagents. Sixteen patients with different refractory solid cancers received up to three distinct neoTCR transgenic cell products. Each product expressed a patient-specific neoTCR and was administered in a cell-dose-escalation, first-in-human phase I clinical trial (NCT03970382). One patient had grade 1 cytokine release syndrome and one patient had grade 3 encephalitis. All participants had the expected side effects from the lymphodepleting chemotherapy. Five patients had stable disease and the other eleven had disease progression as the best response on the therapy. neoTCR transgenic T cells were detected in tumour biopsy samples after infusion at frequencies higher than the native TCRs before infusion. This study demonstrates the feasibility of isolating and cloning multiple TCRs that recognize mutational neoantigens. Moreover, simultaneous knockout of the endogenous TCR and knock-in of neoTCRs using single-step, non-viral precision genome-editing are achieved. The manufacture of neoTCR engineered T cells at clinical grade, the safety of infusing up to three gene-edited neoTCR T cell products and the ability of the transgenic T cells to traffic to the tumours of patients are also demonstrated.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Non-viral precision T cell receptor replacement for personalized cell therapy

Foy¹,

Jacoby²,

Bota

et al. 2022

Nature

133

108

View full text Add to dashboard Cite

show abstract

“…Recently, four early-phase studies presented at ESMO Congress 2022 could represent a step forward in the development of CAR-T cell therapy into solid tumors ( Table 2 ). Different approaches were tested: in two studies CAR-T cell therapies ( 100 , 101 ) were used, a vaccine-targeted therapy in a third trial ( 102 ) and a T-cell receptor T-cell therapy in the fourth one ( 103 ), respectively. Among them, only one enrolled GCT patients ( 100 ).…”

Section: Immunotherapeutic Approaches To Gct Treatmentmentioning

confidence: 99%

Immune checkpoint inhibitors and Chimeric Antigen Receptor (CAR)-T cell therapy: Potential treatment options against Testicular Germ Cell Tumors

Schepisi

Gianni²,

Cursano³

et al. 2023

Front. Immunol.

View full text Add to dashboard Cite

Germ cell tumors (GCTs) represent a heterogeneous neoplasm family affecting gonads and rarely occurring in extragonadal areas. Most of patients have a good prognosis, often even in the presence of metastatic disease; however, in almost 15% of cases, tumor relapse and platinum resistance are the main challenges. Thus, novel treatment strategies with both improved antineoplastic activity and minor treatment-related adverse events compared with platinum are really expected. In this context, the development and the high activity demonstrated by immune checkpoint inhibitors in solid tumors and, subsequently, the interesting results obtained from the use of chimeric antigen receptor (CAR-) T cell therapy in hematological tumors, have stimulated research in this direction also in GCTs. In this article, we will analyze the molecular mechanisms underlying the immune action in the development of GCTs, and we will report the data from the studies that tested the new immunotherapeutic approaches in these neoplasms.

show abstract

“…Additionally, variable and constantly changing levels of antigen expression in different tumor sites further affect CAR-T cell activity. Even worse, TAA are commonly found at low levels on normal tissues, resulting in cross reactions (i.e., “OFF target” and “ON target OFF tumor”) with regional non-tumor cells and severe damage to healthy tissues (Hong et al 2022 ).…”

Section: Overcoming Challenges Of Car-t Cell Therapy In Solid Tumorsmentioning

confidence: 99%

Comprehensive clinical evaluation of CAR-T cell immunotherapy for solid tumors: a path moving forward or a dead end?

Drougkas

Karampinos

Karavolias

et al. 2022

J Cancer Res Clin Oncol

View full text Add to dashboard Cite

Introduction Chimeric Antigen Receptor (CAR)-T cell therapy is a form of adoptive cell therapy that has demonstrated tremendous results in the treatment of hematopoietic malignancies, leading to the US Food and Drug Administration (FDA) approval of four CD19-targeted CAR-T cell products. With the unprecedented success of CAR-T cell therapy in hematological malignancies, hundreds of preclinical studies and clinical trials are currently undergoing to explore the translation of this treatment to solid tumors. However, the clinical experience in non-hematologic malignancies has been less encouraging, with only a few patients achieving complete responses. Tumor-associated antigen heterogeneity, inefficient CAR-T cell trafficking and the immunosuppressive tumor microenvironment are considered as the most pivotal roadblocks in solid tumor CAR-T cell therapy. Materials and methods We reviewed the relevant literature/clinical trials for CAR-T cell immunotherapy for solid tumors from Pubmed and ClinicalTrials.gov. Conclusion Herein, we provide an update on solid tumor CAR-T cell clinical trials, focusing on the studies with published results. We further discuss some of the key hurdles that CAR-T cell therapy is encountering for solid tumor treatment as well as the strategies that are exploited to overcome these obstacles.

show abstract

735MO Updated safety and efficacy from SURPASS, the phase I trial of ADP-A2M4CD8, a next-generation autologous T-cell receptor T-cell therapy, in previously treated patients with unresectable or metastatic tumors

Cited by 4 publications

References 0 publications

Non-viral precision T cell receptor replacement for personalized cell therapy

Non-viral precision T cell receptor replacement for personalized cell therapy

Immune checkpoint inhibitors and Chimeric Antigen Receptor (CAR)-T cell therapy: Potential treatment options against Testicular Germ Cell Tumors

Comprehensive clinical evaluation of CAR-T cell immunotherapy for solid tumors: a path moving forward or a dead end?

Contact Info

Product

Resources

About