RESUMO
Adoptive cell therapy (ACT) for cancer shows tremendous potential; however, several challenges preclude its widespread use. These include poor T-cell function in hostile tumor microenvironments, a lack of tumor-specific target antigens, and the high cost and poor scalability of cell therapy manufacturing. Creative genome-editing strategies are beginning to emerge to address each of these limitations, which has initiated the next generation of cell therapy products now entering clinical trials. CRISPR is at the forefront of this revolution, offering a simple and versatile platform for genetic engineering. This review provides a comprehensive overview of CRISPR applications that have advanced ACT. SIGNIFICANCE: The clinical impact of ACT for cancer can be expanded by implementing specific genetic modifications that enhance the potency, safety, and scalability of cellular products. Here we provide a detailed description of such genetic modifications, highlighting avenues to enhance the therapeutic efficacy and accessibility of ACT for cancer. Furthermore, we review high-throughput CRISPR genetic screens that have unveiled novel targets for cell therapy enhancement.
Assuntos
Sistemas CRISPR-Cas , Terapia Baseada em Transplante de Células e Tecidos/métodos , Edição de Genes/métodos , Imunoterapia Adotiva/métodos , Neoplasias/terapia , Animais , Antígenos de Neoplasias/genética , Antígenos de Neoplasias/metabolismo , Terapia Baseada em Transplante de Células e Tecidos/efeitos adversos , Ensaios Clínicos como Assunto , Terapia Combinada , Gerenciamento Clínico , Avaliação Pré-Clínica de Medicamentos , Engenharia Genética , Terapia Genética , Humanos , Imunoterapia Adotiva/efeitos adversos , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T/imunologia , Receptores de Antígenos de Linfócitos T/metabolismo , Receptores de Antígenos Quiméricos/genética , Receptores de Antígenos Quiméricos/imunologia , Receptores de Antígenos Quiméricos/metabolismo , Linfócitos T/imunologia , Linfócitos T/metabolismo , Resultado do TratamentoRESUMO
Background Treatment of recurrent, unresectable granulosa cell tumor (GCT) of the ovary can be challenging. Given the rarity of the tumor, alternative therapies have been difficult to evaluate in large prospective clinical trials. Currently, to our knowledge, there are no reports of the use of immune checkpoint inhibitors in GCT patients. Here, we present a case series of GCT patients treated with pembrolizumab who were enrolled in a phase II basket trial in advanced, rare solid tumors (ClinicalTrials.gov: NCT02721732). Cases We identified 5 patients with recurrent GCT (4 adult and 1 juvenile type); they had an extensive history of systemic therapy at study enrollment (range, 3-10), with most regimens resulting in less than 12 months of disease control. Pembrolizumab was administered in these patients, as per trial protocol. Although there were no objective responses according to the irRECIST guidelines, 2 patients with adult-type GCT experienced disease control for ≥ 12 months (565 and 453 days). In one, pembrolizumab represented the longest duration of disease control compared to prior lines of systemic therapy (565 days vs. 13 months). In the other, pembrolizumab was the second longest systemic therapy associated with disease control (453 days vs. 22 months) compared to prior lines of therapy. In this patient, pembrolizumab was discontinued following withdrawal of consent. PD-L1 expression was not observed in any baseline tumor samples. Pembrolizumab was well tolerated, with no grade 3 or 4 treatment-related adverse events. Conclusions Although our results do not support the routine use of pembrolizumab monotherapy in unselected GCT patients, some patients with adult-type GCT may derive a clinical benefit, with a low risk of toxicity. Future studies should investigate the role of immunotherapy and predictors of clinical benefit in this patient population.
Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Tumor de Células da Granulosa/tratamento farmacológico , Inibidores de Checkpoint Imunológico/uso terapêutico , Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Adulto , Idoso , Anticorpos Monoclonais Humanizados/efeitos adversos , Proteínas Mutadas de Ataxia Telangiectasia/genética , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/imunologia , Feminino , Proteína Forkhead Box L2/genética , Tumor de Células da Granulosa/genética , Tumor de Células da Granulosa/imunologia , Humanos , Inibidores de Checkpoint Imunológico/efeitos adversos , Linfócitos do Interstício Tumoral/imunologia , Pessoa de Meia-Idade , Mutação , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/imunologia , Neurofibromina 1/genética , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/imunologia , Resultado do Tratamento , Proteína Supressora de Tumor p53/genética , Adulto JovemRESUMO
There is mounting evidence that the immune system plays an important role in the development and growth of gynecologic malignancies, and preliminary studies show activity of immune checkpoint inhibitors in ovarian, endometrial, and cervix cancer. In this review, we outline the completed trials of immune checkpoint blockade in the treatment of gynecologic malignancies. In addition, we review the ongoing trials in each disease site. The questions of which patients will benefit from immune checkpoint inhibitors and when immune checkpoint inhibitors should be incorporated into the treatment of gynecologic malignancies continue to be largely unanswered. As preclinical and clinical data emerge regarding predictive markers for response and resistance to immune checkpoint inhibitors, rational combination treatment strategies will help to further develop this emerging field in the treatment of gynecologic malignancies.