Fabio Petrocca's research while affiliated with Cambridge and other places

Publications (58)

Article
Full-text available
Idecabtagene vicleucel (ide-cel) is a B-cell-maturation antigen (BCMA)-directed chimeric antigen receptor T cell therapy. We performed a post hoc analysis of a single-arm phase 1 multicenter study in relapsed/refractory multiple myeloma (CRB-401) (n = 62; median follow-up, 18.1 months). The primary endpoint was safety outcomes, and secondary endpoi...
Article
b>Hintergrund: Über das Risiko einer Virusinfektion mit dem schweren akuten Atemwegssyndrom Coronavirus 2 (SARS-CoV-2) bei Krebspatienten, von denen viele immungeschwächt und damit anfälliger für eine Vielzahl von Infektionen sind, ist sehr wenig bekannt. Als Vorsichtsmaßnahme haben viele klinische Studien während der ersten Welle der weltweiten Pa...
Article
Introduction: Idecabtagene vicleucel (ide-cel, bb2121) is the first chimeric antigen receptor (CAR) T cell therapy approved for the treatment of relapsed or refractory multiple myeloma after four or more prior lines of therapy, including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 monoclonal antibody. bb21217 is a B-cell mat...
Article
8016 Background: Patients (pts) with RRMM previously exposed to immunomodulatory agents, proteasome inhibitors (PIs), and CD38 antibodies (mAbs) have poor outcomes with subsequent treatments. Ide-cel, a BCMA-directed CAR T cell therapy, showed frequent, deep, and durable responses in heavily pretreated pts with RRMM in the pivotal KarMMa trial (Mun...
Article
Full-text available
Background Idecabtagene vicleucel (ide-cel, also called bb2121), a B-cell maturation antigen–directed chimeric antigen receptor (CAR) T-cell therapy, has shown clinical activity with expected CAR T-cell toxic effects in patients with relapsed and refractory multiple myeloma. Methods In this phase 2 study, we sought to confirm the efficacy and safe...
Article
Full-text available
Background Very little is known about the risk that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral infection poses to cancer patients, many of whom are immune compromised causing them to be more susceptible to a host of infections. As a precautionary measure, many clinical studies halted enrollment during the initial surge of th...
Article
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BCMA targeting chimeric antigen receptor (CAR) T cell therapy has shown deep and durable responses in multiple myeloma. However, relapse following therapy is frequently observed, and mechanisms of resistance remain ill-defined. Here, we perform single cell genomic characterization of longitudinal samples from a patient who relapsed after initial CA...
Article
Introduction: Chimeric antigen receptor (CAR) T cell therapy directed against B-cell maturation antigen (BCMA) has shown promising results for the treatment of relapsed refractory multiple myeloma (RRMM). bb21217 is an anti-BCMA CAR T cell therapy that uses the same CAR molecule as idecabtagene vicleucel (bb2121), but adds the PI3K inhibitor bb007...
Article
Introduction: B-cell maturation antigen (BCMA) is primarily expressed by malignant and normal plasma cells, making it an attractive target for the treatment of multiple myeloma (MM). bb21217 is a BCMA-directed chimeric antigen receptor (CAR) T cell therapy that uses the same CAR molecule as idecabtagene vicleucel (ide-cel, bb2121), but adds the PI3...
Article
Background: Ide-cel, a BCMA-directed CAR T cell therapy, showed tolerability and promising efficacy in patients with relapsed and/or refractory multiple myeloma (RRMM) in the first-in-human phase 1 CRB-401 study (Raje et al. N Engl J Med. 2019;380:1726) and the pivotal phase 2 KarMMa study (Munshi et al. J Clin Oncol. 2020;38[suppl, abstr]:8503). I...
Article
Chimeric antigen receptor (CAR) T-cell therapy targeting B cell maturation antigen (BCMA) has provided deep (73% - 100%) responses in relapsed/refractory multiple myeloma (MM). However, median PFS has been less than 12 months, and amongst the small number of patients retreated at the time of progression with the same CAR T product, responses have b...
Article
8503 Background: Outcomes are poor in triple-class exposed RRMM patients (pts) who progress on immunomodulatory agents (IMiDs), proteasome inhibitors (PIs), and CD38 antibodies (mAbs). Ide-cel, a BCMA targeted CAR T cell therapy, showed promising tolerability and efficacy in RRMM pts in the phase I CRB-401 study ( NEJM2019;380:1726). We present pri...
Article
Introduction: Chimeric antigen receptor (CAR) T cell therapy directed against B cell maturation antigen (BCMA) has shown promising results for the treatment of relapsed refractory multiple myeloma (RRMM) in several phase 1 studies. Persistence of CAR T cells post infusion may be one determinant of duration of response. bb21217 is a next-generation...
Article
Background Preclinical studies suggest that bb2121, a chimeric antigen receptor (CAR) T-cell therapy that targets B-cell maturation antigen (BCMA), has potential for the treatment of multiple myeloma. Methods In this phase 1 study involving patients with relapsed or refractory multiple myeloma, we administered bb2121 as a single infusion at doses...
Article
Introduction: Immunomodulatory chimeric antigen receptor (CAR) T cell therapy directed against B-cell maturation antigen (BCMA) has shown promising results for the treatment of relapsed refractory multiple myeloma (RRMM) in several phase 1 clinical studies in patients with advanced disease. Persistence of CAR T cells post infusion may be one determ...
Article
Prognosis of triple-negative breast cancer (TNBC) remains poor. To identify shared and selective vulnerabilities of basal-like TNBC, the most common TNBC subtype, a directed siRNA lethality screen was performed in 7 human breast cancer cell lines, focusing on 154 previously identified dependency genes of one TNBC line. Thirty common dependency gene...
Article
Full-text available
Chimeric Antigen Receptor (CAR) T-cells are T-cells with recombinant receptors targeted to tumor antigens. CAR-T cell therapy has emerged as a mode of immunotherapy and is now being extensively explored in hematologic cancer. In contrast, CAR-T cell use in solid tumors has been hampered by multiple obstacles. Several approaches have been taken to c...
Article
Triple negative breast cancers (TNBC) account for ~15% of all breast cancers and the majority of breast cancers in women carrying a BRCA1 germline mutation. Due to the inadequacy of existing treatment, here we sought to identify shared genetic dependencies across different TNBC cell lines with the ultimate goal of uncovering novel therapeutic targe...
Article
Triple-negative breast cancers (TNBC) are the most aggressive subtype of breast cancer and account for roughly 15% of human breast cancers. No effective targeted therapies are currently available against these tumors, at least in part due to their genetic and epigenetic heterogeneity. Yet, TNBCs are commonly enriched for cells arrested in a progeni...
Article
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Tumours are comprised of a highly heterogeneous population of cells, of which only a small subset of stem-like cells possess the ability to regenerate tumours in vivo. These cancer stem cells (CSCs) represent a significant clinical challenge as they are resistant to conventional cancer therapies and play essential roles in metastasis and tumour rel...
Article
Effective therapeutic strategies for in vivo siRNA delivery to knockdown genes in cells outside the liver are needed to harness RNA interference for treating cancer. EpCAM is a tumor-associated antigen highly expressed on common epithelial cancers and their tumor-initiating cells (T-IC, also known as cancer stem cells). Here we show that aptamer-si...
Article
The miR-200 family promotes the epithelial state by suppressing the Zeb1/Zeb2 epithelial gene transcriptional repressors. To identify other miR-200-regulated genes, we isolated mRNAs bound to transfected biotinylated miR-200c in mouse breast cancer cells. In all, 520 mRNAs were significantly enriched in miR-200c binding at least twofold. Putative m...
Article
There is no targeted therapy for triple negative breast cancers (TNBC), which have the worst prognosis of human breast cancers. TNBCs are prone to relapse and metastasize after cytotoxic drug treatment. This group of cancers, defined by low or absent expression of estrogen, progesterone and Her2 receptors, are heterogeneous in genetic, epigenetic a...
Article
RNA interference (RNAi) offers the exciting therapeutic possibility of selectively knocking down disease-causing genes. Recent Phase I and II clinical trials of small interfering RNAs (siRNAs) have shown promising gene knockdown and clinical benefit in a handful of diverse diseases caused by aberrant liver gene expression. In these studies siRNAs w...
Article
Basal-like triple-negative breast cancers (TNBCs) have poor prognosis. To identify basal-like TNBC dependencies, a genome-wide siRNA lethality screen compared two human breast epithelial cell lines transformed with the same genes: basal-like BPLER and myoepithelial HMLER. Expression of the screen's 154 BPLER dependency genes correlated with poor pr...
Article
Cancer therapeutics still fall far short of our goals for treating patients with locally advanced or metastatic disease. Until recently, almost all cancer drugs were crude cytotoxic agents that discriminate poorly between cancer cells and normally dividing cells. The development of targeted biologics that recognize tumor cell surface antigens and o...
Article
MicroRNAs (miRNAs) regulate cell fate during development and in response to environmental cues. Here, we review the emerging story of how miRNAs regulate immune cell development and function.
Data
PCNA staining of representative primary tumors and metastases from BALB/c mice. Tumors and metastases derived from implanted 4T1 cells or 4TO7 cells that were unmodified or infected with retroviruses expressing a control miR-30 stem insert or the miR-141-200c miRNA cluster within the miR-30 stem were stained with PCNA. (0.89 MB TIF)
Article
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The development of metastases involves the dissociation of cells from the primary tumor to penetrate the basement membrane, invade and then exit the vasculature to seed, and colonize distant tissues. The last step, establishment of macroscopic tumors at distant sites, is the least well understood. Four isogenic mouse breast cancer cell lines (67NR,...
Data
The Zeb1 3′-UTR is a target of the miR-200 family of miRNAs. Cells were co-transfected with psiCheck2 vector that contains the full length Zeb1 3′-UTR and with miR-200b and/or miR-200c miRNA mimics. Renilla luciferase expression was normalized to firefly luciferase and the ratio then normalized to that of mock-transfected cells (*, p<0.0002). (0.04...
Data
miRNA expression profile of the mouse mammary tumor cell lines based on miRNA microarray analysis. miRNAs reporter names are referred to by their names in miRbase v9.0. Two biological samples for each tumor cell lines were used and two independent hybridizations (Trial 1 and Trial 2) were performed. The dynamic range for the microarray platform is...
Data
Primers and siRNA sequences. (0.03 MB XLS)
Article
Because microRNAs regulate cancer cell differentiation, proliferation, survival and metastasis, manipulating microRNA function, either by mimicking or inhibiting miRNAs implicated in cancer, could provide a powerful therapeutic strategy to interfere with key pathways for cancer progression. This review will explore some of the opportunities and obs...
Article
MicroRNAs (miRNAs) regulate cell fate during development and in response to environmental cues. Here, we review the emerging story of how miRNAs regulate immune cell development and function.
Article
Full-text available
The High Mobility Group proteins HMGA1 are nuclear architectural factors that play a critical role in a wide range of biological processes. Since recent studies have identified the microRNAs (miRNAs) as important regulators of gene expression, modulating critical cellular functions such as proliferation, apoptosis and differentiation, the aim of ou...
Article
MicroRNAs (miRNAs) are small, noncoding RNAs controlling the activity of 30% of all proteincoding genes by inhibiting target mRNA translation and inducing its degradation. Growing evidence demonstrates that miRNAs take part in regulating almost every cellular process, and that aberrant miRNA expression is a hallmark of disease, including human canc...
Article
A small interfering RNA has been engineered to silence an oncogene and activate the immune response simultaneously. The approach shrinks tumors in mice (pages 1256–1263).
Article
Inactivation of the transforming growth factor beta (TGFbeta) tumor suppressor pathway is a main step in the development of a variety of human tumors. The miR-106b-25 and miR-17-92 clusters are emerging as key modulators of TGFbeta signaling in gastrointestinal and other tumors, interfering with cell cycle arrest and apoptosis when overexpressed in...
Article
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MicroRNAs are small noncoding RNAs that regulate the expression of protein-coding genes. To evaluate the involvement of microRNAs in prostate cancer, we determined genome-wide expression of microRNAs and mRNAs in 60 primary prostate tumors and 16 nontumor prostate tissues. The mRNA analysis revealed that key components of microRNA processing and se...
Article
Deregulation of E2F1 activity and resistance to TGFbeta are hallmarks of gastric cancer. MicroRNAs (miRNAs) are small noncoding RNAs frequently misregulated in human malignancies. Here we provide evidence that the miR-106b-25 cluster, upregulated in a subset of human gastric tumors, is activated by E2F1 in parallel with its host gene, Mcm7. In turn...
Article
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Thyroid carcinomas comprise a broad spectrum of tumors with different clinical behaviors. On the one side, there are occult papillary carcinomas (PTC), slow growing and clinically silent, and on the other side, rapidly growing anaplastic carcinomas (ATC), which are among the most lethal human neoplasms. We have analysed the microRNA (miR) profile o...
Article
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Epithelial ovarian cancer (EOC) is the sixth most common cancer in women worldwide and, despite advances in detection and therapies, it still represents the most lethal gynecologic malignancy in the industrialized countries. Unfortunately, still relatively little is known about the molecular events that lead to the development of this highly aggres...
Article
We have recently reported that MicroRNAs (miR)-221 and miR-222 were up-regulated in human thyroid papillary carcinomas in comparison with the normal thyroid tissue. Bioinformatic analysis proposed the p27(Kip1) protein, a key regulator of cell cycle, as a candidate target for the miR-221/222 cluster. Here, we report that the enforced expression of...
Article
While global microRNA (miRNA) expression patterns of many embryologic, physiologic, and oncogenic processes have been described, description of the role of miRNAs in ductal adenocarcinoma of the pancreas is lacking. To define the expression pattern of miRNAs in pancreatic cancer and compare it with those of normal pancreas and chronic pancreatitis....
Article
AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA 4534 Recent success in genetic manipulation to transform normal human cells has provided a strong experimental approach to investigate the changes that occur and contribute to human mammary tumorigenesis. To gain more insight into the role of tumor suppressor BRCA1 in human breast tumorigene...
Article
The FEZ1/LZTS1 (LZTS1) protein is frequently downregulated in human cancers of different histotypes. LZTS1 is expressed in normal tissues, and its introduction in cancer cells inhibits cell growth and suppresses tumorigenicity, owing to an accumulation of cells in G2/M. Here, we define its role in cell cycle regulation and tumor progression by gene...
Article
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ARLTS1 is a tumor suppressor gene initially described as a low-penetrance cancer gene: a truncated Trp149Stop (MUT) polymorphism is associated with general familial cancer aggregation and, particularly, high-risk familial breast cancer. DNA hypermethylation has been identified as a mechanism of ARLTS1 expression down-regulation in lung carcinomas a...
Article
Full-text available
Small noncoding microRNAs (miRNAs) can contribute to cancer development and progression and are differentially expressed in normal tissues and cancers. From a large-scale miRnome analysis on 540 samples including lung, breast, stomach, prostate, colon, and pancreatic tumors, we identified a solid cancer miRNA signature composed by a large portion o...

Citations

... The anti-CD30 CAR-T cells have also been developed in HL, [435][436][437] and more clinical trials are being conducted to verify their efficacy. In addition to lymphoma and leukemia, CAR-T cells have also made great progress in treatment of MM. 278,[438][439][440][441][442][443][444][445][446] Idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel (cilta-cel) have already been approved by the FDA based on responses and safety demonstrated in the KarMMa and CARTITUDE-1 trials. 439,440,442 Meanwhile, more companies have launched CAR-T cell products for MM, such as orva-cel, P-BCMA-101. ...
... However, despite these advances, myeloma remains mostly a chronic disease with most patients experiencing serial relapse 1,24 . Recent discoveries in targeted immunotherapy have shown promise in improving clinical outcomes for some patients, but their utility is limited due to adverse side effects from off-target toxicity, increased therapy resistance, and tumor escape [26][27][28][29][30][31][32][33][34][35][36][37] . Increased immunosuppression of the tumor microenvironment can also negatively impact tumor progression and targeted therapy response [38][39][40][41][42][43] . ...
... In the pivotal phase 2 KarMMa trial, patients infused with ide-cel achieved an ORR of 73%, ≥ complete response (CR) rate of 33%, median progression-free survival (PFS) of 8.6 months, and median OS of 24.8 months [5,12]. This consortium has previously published retrospective outcomes for the largest cohort of patients treated with commercially available ide-cel in a real-world setting. ...
... However, if the cause of LEN refractoriness is a gene mutation, such as CRBN, PI might be a suitable option. Currently, the detection of new drugs for suitable targets, such as B-cell mature antigen (BCMA) [103][104][105], G protein-coupled receptor class C group 5D (GPRC5D) [106,107], and Fc receptor-homolog 5 (FcRH5) [108], is developing. Additionally, specific gene mutations such as v-raf murine sarcoma viral oncogene homolog B1 (BRAF) and cytogenetic abnormalities such as t (11;14) are identified in myeloma cells, where BRAF inhibitors and venetoclax may be effective [109][110][111][112][113]. Therefore, suitability of future therapies can be improved through the characterization of gene mutations, the IMiD sensitivity considering the previous LEN duration and dose, the immunological environment, and the presence of new targeting molecules. ...
... In one patient suffering from multiple myeloma, fatal outcome after BCMA-directed CAR T-cell therapy due to prolonged SARS-CoV-2 RNAemia and acute respiratory distress syndrome (ARDS) has been described (3). The other reported patient received the same anti-BCMA CAR T-cell therapy for multiple myeloma and developed a sustained antibody response and survived SARS-CoV-2 infection (4). ...
... However, this therapy is not curative either, in line with other single-targeted therapies [10][11][12][13] . Recent evidence suggests that some patients treated with BCMA CAR T cells relapse with BCMAnegative disease, or antigen escape [14][15][16][17] . In addition, there is evidence that BCMA is strongly downregulated and trogocytosed after exposure to BCMA CAR T cell therapies, suggesting that targeting of a second antigen may be warranted 18 . ...
... Intra-tumoral BCMA heterogeneity can lead to the selection and proliferation of clones with low/no BCMA expression as MM cells with high BCMA expression are preferentially killed [133][134][135]. This is consistent with studies reporting loss of BCMA upon disease relapse after the first CAR T-cell infusion [136][137][138][139]. Antigen escape can occur because of permanent antigen loss from alternative splicing or heterozygous deletion of chromosome 16p and concomitant frameshift or missense mutation of the other allele [138,140,141], or reversible antigen loss through trogocytosis (active transfer of target antigen to T cells), increasing the risk of T-cell fratricide and exhaustion [142][143][144]. ...
... 29 In their trial of BCMA-targeting CD28ζ CAR, Cohen et al describe between 20% and 30% of naive and stem cell memory T-cell populations 9 and this figure was under 10% with ide-cel. 30 Looking for a further reason for the low clinical responses, we also noted that BCMA expression was not a criteria for trial entry in the AUTO2 trial in common to other BCMA CAR trials. 13 24 Thus the high proportion of mature memory phenotypes, low TEs observed and no requirement for tumor BCMA expression for trial entry were not unique to AUTO2 and could not sufficiently explain the low response rates in the AUTO2 trial. ...
... No treatment-related deaths occurred [36]. After a median follow-up time of 14.7 months, the median PFS was 8.8 months and the median OS was 34.2 months [37]. Adequate responses were observed at all doses. ...