PSMA-targeting TGFβ-insensitive armored CAR T cells in metastatic castration-resistant prostate cancer: a phase 1 trial

Narayan, Vivek; Barber‐Rotenberg, Julie S.; Jung, In-Young; Lacey, Simon F.; Rech, Andrew J.; Davis, Megan M.; Hwang, Wei–Ting; Lal, Priti; Carpenter, Erica L.; Maude, Shannon L.; Plesa, Gabriela; Vapiwala, Neha; Chew, Anne; Moniak, Michael; Sebro, Ronnie; Farwell, Michael D.; Marshall, Amy; Gilmore, Joan; Lledo, Lester; Dengel, Karen; Church, S.; Hether, Tyler; Xu, Jun; Gohil, Mercy; Buckingham, Thomas H.; Yee, Stephanie S.; Gonzalez, Vanessa; Kulikovskaya, Irina; Chen, Fang; Tian, Lifeng; Tien, Kyle; Gladney, Whitney L.; Nobles, Christopher L.; Raymond, Hayley E.; Hexner, Elizabeth O.; Siegel, Donald L.; Bushman, Frederic D.; June, Carl H.; Fraietta, Joseph A.; Haas, Naomi B.

doi:10.1038/s41591-022-01726-1

Cited by 244 publications

(166 citation statements)

References 79 publications

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“…The immunologically 'cold' tumor microenvironment of prostate cancer is a major barrier to the efficacy of cancer immunotherapies including immune checkpoint inhibitors. In addition, exploratory studies associated with a phase I clinical trial of PSMA CAR T cell therapy armored to express dominant-negative transforming growth factor-β receptor (TGFβR-DN) in mCRPC showed that the expression of immunosuppressive signaling molecules in the tumor microenvironment increases after CAR T infusion 9 . In our work, we have used a disseminated, syngeneic RM9-hSTEAP1 tumor model in hSTEAP1-KI to approximate the immunosuppressive nature of mCRPC based on prior characterization of RM9 as a poorly immunogenic model 52,60 .…”

Section: Discussionmentioning

confidence: 99%

“…In contrast, CAR T cell therapies targeting solid tumors have lagged due to additional challenges related to the lack of bona fide tumor-specific antigens, inhospitable tumor microenvironments, and poor trafficking, persistence, and expansion of CAR T cells. Despite the challenges observed in driving effective immune responses toward solid tumors, recent early phase clinic trials investigating CAR T cell therapies targeting PSMA in mCRPC have reported safety and evidence of significant biochemical and radiographic responses 8,9 .…”

Section: Introductionmentioning

confidence: 99%

“…Despite the challenges observed in driving effective immune responses toward solid tumors, recent early phase clinic trials investigating CAR T cell therapies targeting PSMA in mCRPC have reported safety and evidence of significant biochemical and radiographic responses 8, 9 . These preliminary results serve to embolden efforts to develop and optimize new CAR T cell therapies for prostate cancer.…”

Section: Introductionmentioning

confidence: 99%

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Targeting advanced prostate cancer with STEAP1 chimeric antigen receptor T cell therapy

Bhatia

Kamat

Pariva

et al. 2022

Preprint

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SummarySix transmembrane epithelial antigen of the prostate 1 (STEAP1) is a compelling tumor-associated cell surface antigen for therapeutic targeting in solid tumors. We identified broad expression of STEAP1 (87% positive) in lethal metastatic prostate cancer, even more so than prostate-specific membrane antigen (PSMA, 60% positive) which is a clinically established diagnostic and therapeutic target. Second-generation chimeric antigen receptor (CAR) T cells were engineered for reactivity against STEAP1 and demonstrated substantial antitumor activity in metastatic human prostate cancer models in immunodeficient mice. Adoptive transfer of STEAP1 CAR T cells was associated with prolonged peripheral persistence and either disease eradication or substantial tumor growth inhibition with progressive disease demonstrating antigen loss. As STEAP1 CAR T cells were also highly active in antigen density conditions as low as ∼1,500 molecules/cell, we generated a human STEAP1 (hSTEAP1) knock-in (KI) mouse to evaluate the potential for on-target off-tumor toxicities. hSTEAP1-KI mice demonstrated a pattern of systemic hSTEAP1 expression akin to that observed in humans with the greatest expression found in the prostate gland. Mouse-in-mouse studies of STEAP1 CAR T cell therapy in immunocompetent hSTEAP1-KI mice engrafted with disseminated mouse prostate cancer showed preliminary safety without evidence of gross toxicity, cytokine storm, or architectural disruption and increased T cell infiltration at sites of systemic hSTEAP1 expression. Tumor responses and extension of survival were appreciated but antigen loss was identified in recurrent and progressive disease. In summary, we report the extent of STEAP1 expression in treatment-refractory metastatic prostate cancer, the generation of a STEAP1 CAR T cell therapy with promising potency and safety in preclinical studies of advanced prostate cancer, and antigen escape as a mechanism of resistance to effective STEAP1 CAR T cell therapy.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Targeting advanced prostate cancer with STEAP1 chimeric antigen receptor T cell therapy

Bhatia

Kamat

Pariva

et al. 2022

Preprint

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“…Recently, Narayan and colleagues reported results from an in-human phase I trial of castration-resistant, prostate cancer-directed CAR-T cells armored with a dominant-negative TGF-β receptor ( 120 ). CAR-T cell kinetics revealed expansion in blood and tumor trafficking, proving that a clinical application of TGF-β-resistant CAR-T cells is feasible and generally safe, suggesting a novel strategy to improve therapy outcomes by a superior multipronged approach against the TME.…”

Section: Adoptive Cell Transfer–based Therapymentioning

confidence: 99%

Progress and Prospect of Immunotherapy for Triple-Negative Breast Cancer

Luo

Wang

et al. 2022

Front. Oncol.

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Breast cancer is the most commonly diagnosed cancer (estimated 2.3 million new cases in 2020) and the leading cause of cancer death (estimated 685,000 deaths in 2020) in women globally. Breast cancers have been categorized into four major molecular subtypes based on the immunohistochemistry (IHC) expression of classic hormone and growth factor receptors including the estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2), as well as a proliferation marker Ki-67 protein expression. Triple-negative breast cancer (TNBC), a breast cancer subtype lacking ER, PR, and HER2 expression, is associated with a high metastatic potential and poor prognosis. TNBC accounts for approximately only 15%–20% of new breast cancer diagnoses; it is responsible for most breast cancer–related deaths due to the lack of targeted treatment options for this patient population, and currently, systemic chemotherapy, radiation, and surgical excision remain the major treatment modalities for these patients with TNBC. Although breast cancer patients in general do not have a robust response to the immunotherapy, a subset of TNBC has been demonstrated to have high tumor mutation burden and high tumor-infiltrating lymphocytes, resembling the features observed on melanoma or lung cancers, which can benefit from the treatment of immune checkpoint inhibitors (ICIs). Therefore, the immunogenic nature of this aggressive disease has presented an opportunity for the development of TNBC-targeting immunotherapies. The recent US Food and Drug Administration approval of atezolizumab in combination with the chemotherapeutic agent nab-paclitaxel for the treatment of PD-L1-positive unresectable, locally advanced, or metastatic TNBC has led to a new era of immunotherapy in TNBC treatment. In addition, immunotherapy becomes an active research area, both in the cancer biology field and in the oncology field. In this review, we will extend our coverage on recent discoveries in preclinical research and early results in clinical trials from immune molecule-based therapy including cytokines, monoclonal antibodies, antibody–drug conjugates, bi-specific or tri-specific antibodies, ICIs, and neoantigen cancer vaccines; oncolytic virus-based therapies and adoptive immune cell transfer–based therapies including TIL, chimeric antigen receptor-T (CAR-T), CAR-NK, CAR-M, and T-cell receptor-T. In the end, we will list a series of the challenges and opportunities in immunotherapy prospectively and reveal novel technologies such as high-throughput single-cell sequencing and CRISPR gene editing-based screening to generate new knowledges of immunotherapy.

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“…CRISPR/ Cas9-edited TGF-β R2 enhances the anti-tumor capability of CAR-T cells by reducing the transformation of Tregs and T cell exhaustion [93] . Thirteen patients with metastatic castration-resistant prostate cancer received prostate specific antigen-directed CAR-T cells armored with a dominant-negative TGF-βR; among the patients, five patients experienced grade ≥r CRS, and 4 patients experienced a reduction in prostate-specific antigen level [94] . The density of TAMs is negatively correlated with the prognosis in various types of solid tumors.…”

Section: Immunosuppressive Microenvironmentmentioning

confidence: 99%

Gene-modified T cell therapy for cancer: Current challenges and potential solutions

Chen¹,

Li²,

Zhang³

et al. 2022

GPD

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Immunotherapy has achieved significant breakthroughs in patients with hematological diseases and various cancers. The adoptive transfer of T cells, especially gene-modified T cells such as chimeric antigen receptor T (CAR-T) cells and T cell receptor-engineered T (TCR-T) cells, is developing rapidly. Since 2017, eight CAR-T cell products have been approved for the treatment of hematological diseases, such as refractory or relapsed acute B lymphoblastic leukemia, specific subtypes of B cell lymphoma, and multiple myeloma. The first TCR-T cell product, Kimmtrak, was approved for the treatment of unresectable or metastatic uveal melanoma in March 2022. However, there are still many problems, including side effects, relapse, high demand for individualization, and expensive cost in hematological diseases, tumor heterogeneity, antigen escape, poor immune cell infiltration ability, immunosuppressive microenvironment, and low response in solid tumors. With the in-depth exploration of tumor immunology and the development of genetic engineering technology, many novel strategies for improving the anti-tumor effect and safety of gene-modified T cell immunotherapy have been attempted. This paper presents a systematic review of the literature on CAR-T cell and TCR-T cell therapy, focusing on applications, clinical trials, problems, and potential solutions.

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PSMA-targeting TGFβ-insensitive armored CAR T cells in metastatic castration-resistant prostate cancer: a phase 1 trial

Cited by 244 publications

References 79 publications

Targeting advanced prostate cancer with STEAP1 chimeric antigen receptor T cell therapy

Targeting advanced prostate cancer with STEAP1 chimeric antigen receptor T cell therapy

Progress and Prospect of Immunotherapy for Triple-Negative Breast Cancer

Gene-modified T cell therapy for cancer: Current challenges and potential solutions

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