Primary Human Blood And Cancer
Blood and tumors from patients with PDAC were supplied by the Barts Pancreas Tissue Bank and obtained with written consent from all patients. The collection of human tissue was performed under the Barts Pancreas Tissue Bank Protocol, REC reference 13/SC/0592. PDAC tumors were expanded as patient-derived xenografts in immunocompromised mice as described previously .
Several primary patient-derived PDAC cell cultures were used in this study. PDAC lines 253, 354, 247, 286, 420, A6L, and 185 were gifts from James Eshleman and Christine Iacobuzio-Donahue , PDAC lines 12707, 12556, and 12560 were a gift from Aldo Scarpa . In addition, circulating tumor cell -derived PDAC cell cultures c76, c102, and c139 generated in-house from patients with late stage, chemo-naïve PDAC were also used. Short tandem repeat profiling of all patient-derived PDAC cell lines was performed and confirmed the uniqueness of each of these lines.
To culture spheres enriched in CSCs, cells were resuspended in 1à DMEM/F-12 supplemented with 20 ng/mL FGF-2 , 0.4% amphotericin B, 1% penicillin/streptomycin, 2% B27 supplement , and 200 mmol/L of l-glutamine . A cell suspension of 10,000 cells/mL was then prepared and distributed into ultralow attachment surface flasks for 1 week. Prior to use, spheres were filtered using a 40-μmol/L strainer to remove single cells and aggregates.
Specific Activity Of 2869 Car T Cells Against Ceacam7
The specificity and efficacy of 2869 CAR against CEACAM7-expressing targets was then investigated. Ectopic CEACAM7-expressing 354GL and c102GL cells were used as CAR T-cell targets, with unmodified cells as a negative control. T cells that were unmodified, or modified to express either one of the 2869 CARs, were overlaid on a monolayer of PDAC target cells at a 5:1 E:T ratio. Viability of the target cells was initially assessed by GFP expression. Lysis of CEACAM7-expressing target PDAC cells, but not unmodified cells, was observed following coculture with either of the 2869 CAR T-cell types . Quantitation of target cell viability using WST-1 showed that neither of the 2869 CAR T-cell types had any effect on unmodified PDAC cells, but decreased viability of CEACAM7-expressing targets when applied both at 5:1 and 1:1 E:T ratios. Cytotoxic killing appeared to be antigen density dependent, with higher cytotoxicity observed against c102GL than 354GL, consistent with higher CEACAM7 expression on c102GL cells. The smaller 2869 CAR had a slight but significantly higher cytotoxic efficacy when CAR T cells were applied at the 5:1 E:T ratio on either target cell type . 2869 CAR T cells can therefore specifically target CEACAM7-expressing cells, with no effect on cells that do not express the target antigen.
Primary Human Cancer Cells
Blood and tumours from patients with PDAC were obtained with written consent from all patients. The collection was performed under the Barts Pancreas Tissue Bank Protocol , the Biobank of the Spanish National Cancer Research Centre , Madrid, Spain , the ARC-NET Biobank at the Rossi University of Verona Hospital, Italy , and the biobank at the Department of Surgery, Klinikum Rechts der Isar, Technical University Munich, Germany .
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Researchers Identify Novel Target That Could Improve The Safety Of Car T Cell Therapy For Pancreatic Cancer
Researchers from Barts Cancer Institute , Queen Mary University of London, have identified a protein that may represent a novel therapeutic target for the treatment of pancreatic cancer. Using this protein as a target, the team successfully created a CAR T cell therapy – a type of immunotherapy – that killed pancreatic cancer cells in a pre-clinical model.
CAR T cell therapy is an immunotherapy that has shown great promise for the treatment of some blood cancers however, the treatment of solid tumours using this therapy has proved very difficult. One barrier to success is toxicity in tissues other than the cancer because most of the proteins currently used to target CAR T cells to pancreatic cancer cells and other solid tumours are present in low levels on other normal tissues, leading to toxic side effects.
In this study, published today in Clinical Cancer Research and funded by the charity Pancreatic Cancer UK, the team identified a protein called CEACAM7 that may represent a safer treatment target for the development of therapies against pancreatic ductal adenocarcinoma , the most common type of pancreatic cancer.
To determine the potential of CEACAM7 as a treatment target, the team developed CAR T cells targeted to CEACAM7 and applied these to PDAC cell lines as well as a preclinical model of PDAC. The CAR T cells effectively targeted the CEACAM7-expressing cells in PDAC cell cultures, and eliminated cancer cells in a late-stage preclinical model of PDAC.
About The Treatment Of Pancreatic Cancer
PDAC is the most common type of pancreatic cancer and has the lowest survival rate of all the common cancers, with only a seven percent five-year survival rate. Diagnosis often occurs at a point when surgery to remove the tumour which offers the greatest chance of a cure is not possible. As a result, there is an urgent need for new and more effective targeted therapies.
Chris Macdonald, Head of Research at Pancreatic Cancer UK, the charity which funded the study, said: These findings are very encouraging and offer real hope that a new, innovative immunotherapy treatment for pancreatic cancer is on the horizon. For the first time a distinct and specific target protein for pancreatic cancer cells has been identified and, crucially, the brilliant team at Barts have shown that by focusing on it, they can destroy the cancer without damaging healthy tissue.
He concluded that the study marks an important step towards a desperately needed new treatment option, which could be both more effective and have fewer side-effects for patients and that he looks forward to seeing the outcomes of clinical trials targeting the CEACAM7 protein in future.
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Ceacam7 Is An Effective Target For Car T
*Corresponding Author:
Note: Supplementary data for this article are available at Clinical Cancer Research Online .
Corresponding Author:
Clin Cancer Res 2021 27:1538â52
- Pancreatic Cancer UK Grand Challenge award
Clin Cancer Res
Deepak Raj, Maria Nikolaidi, Irene Garces, Daniela Lorizio, Natalia M. Castro, Sabrina G. Caiafa, Kate Moore, Nicholas F. Brown, Hemant M. Kocher, Xiaobo Duan, Brad H. Nelson, Nicholas R. Lemoine, John F. Marshall CEACAM7 Is an Effective Target for CAR T-cell Therapy of Pancreatic Ductal Adenocarcinoma. Clin Cancer Res 1 March 2021 27 : 1538â1552.
Clincial Experience With Car T Cells In Pancreatic Cancer
Table 1. Recently completed and ongoing clinical trials with CAR T cell therapy in pancreatic cancer.
In a more recent phase I study of CARTmeso cells by the same group, 6 patients with treatment refractory metastatic pancreatic cancer were administered CARTmeso cells intravenously 3 times per week for 3 weeks. In this trial, no dose limiting toxicity, cytokine release syndrome or neurological complications were encountered, while stable disease was reported in two of the patients . These findings were complemented by decreased FDG uptake on PET computed tomography, suggestive of activity against the tumor in these patients. This initial encouraging safety data with a more conservative, transient expression approach of CAR targeting mesothelin has prompted further attempts at targeting this antigen using more stable introduction of lentiviral constructs into T cells . Several other trials are currently open to patients with mesothelin-expressing PDAC to further evaluate CARs directed at this antigen .
What Is Car T Cell Therapy Like For Patients
After the T cells are collected, modifying and multiplying them for infusion usually takes a few weeks. Patients may undergo other cancer treatments during this time.
When the CAR T cells are ready for use, they are sent to the hospital for infusion. Before infusion, patients are given a short course of chemotherapy. This weakens their existing immune system, giving the engineered T cells a better chance of expanding and fighting the cancer.
The infusion of the modified T cells is quick, typically lasting less than an hour.
After infusion, patients must remain near the hospital for at least four weeks. Depending on the patients type of cancer, condition and specific treatment, this time may be spent as an outpatient or a mix of both inpatient and outpatient. All patients must have a caregiver with them at all times to help care for them and monitor for side effects.
Doctors Mark Breakthrough Treatment In Pancreatic Cancer Case
One potential factor that could explain Wilkes’ positive results is that her pancreatic cancer had spread to her lungs rather than her liver, said Dr. Ryan Carr, a pancreatic cancer expert at the Mayo Clinic in Rochester, Minnesota. Carr, who wasn’t involved with Wilkes’ treatment, said that in his experience patients whose tumors spread to the lungs tend to have more favorable outcomes than patients whose cancer spreads to the liver, a more common site of metastasis.
“In most situations, when we have these lung metastases, they don’t really cause symptoms in the patient,” Carr said. “It’s still a poor prognosis, but we know there’s something different about them, and they are a little bit better off than those that spread to the liver.”
As such details are worked out, both June and Carr maintain that the new therapy seems to be a major step forward in the treatment of pancreatic cancer.
“I think cancer research is going to pick up again and going to build on this,” said June, who is director of the Parker Institute for Cancer Immunotherapy at the University of Pennsylvania. “The real question is not if but when this kind of therapy becomes a reality of curing patients with now lethal cancers.”
CORRECTION A previous version of this article misstated which patients would respond to the gene therapy. They are patients with the KRAS mutation plus a specific molecule on the cell surface, not patients with a subtype of the KRAS mutation.
Technique Offered To Certain Patients Facing Recurrence Of Cancer Previously Required Travel Out Of Province
A cancer treatment that previously required travel outside the province, or the country, is now being offered in Alberta.
The first patients to receive CAR T-cell therapy in the province are at the Tom Baker Cancer Centre in Calgary, while the government says a clinical trial to develop a made-in-Alberta CAR T-cell therapy is underway at the Cross Cancer Institute in Edmonton.
The new treatment is funded with $15 million from the government and the Alberta Cancer Foundation. Alberta is now the third province to offer the treatment.
CAR T-cell therapy involves taking the T-cells from a patient, genetically modifying them to fight cancer cells, expanding their numbers in a lab and then re-injecting them into the patient.
“The immunotherapy is a treatment that uses or harnesses the patient’s own immune system to treat cancer, said Dr. Mona Shafey, a clinical associate professor at the University of Calgary and the director of the Alberta blood and marrow transplant program.
“Traditional chemotherapy has failed in these patients and so this is a different technique, a way of trying to get cancer under control,” she said.
The treatment is used for both children and adults with specific types of leukemia and lymphoma.
Car T Cell Therapy Being Tested In Pancreatic Cancer
CURE
Experimental treatment uses engineered T cells to target prostate stem cell antigen.
A FLEDGLING BUT PROMISING form of immunotherapy known as CAR T cell therapy has been adapted to hit a new biologic target in the hopes that it will effectively fight advanced pancreatic cancer. The technique is being tested in a phase 1 trial designed to enroll up to 30 patients with the disease.
In CAR T cell therapy, immune cells, also known as T cells, are removed from a patients body and engineered in a lab to recognize a specific biologic marker that drives a cancer, and to destroy cells that carry it these special T cells are then returned to the patient to multiply and do that work. The therapy being tested in this trial, BPX-601, targets prostate cancer stem cell antigen.
Trial Details
The trial is being conducted solely at Dallas Baylor Sammons Cancer Center, through the Baylor Scott & White Research Institute. It is testing BPX-601 in humans for the first time. Other CAR T cell therapies have already been tested in humans in early-phase trials for a variety of cancer types, but no such therapy has yet been approved by the U.S. Food and Drug Administration.
Rimiducid, developed by Bellicum, is designed to trigger T cell activation and proliferation in patients administered BPX-601. It helps enable control over the activity and potency of the therapy.
Trial Could Open Doors
He added a note of restraint, however.
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Targeted Therapy For Pancreatic Cancer
As researchers have learned more about the changes in pancreatic cancer cells that help them grow, they have developed newer drugs to specifically target these changes. These targeted drugs work differently from standard chemo drugs. Sometimes they work when standard chemo drugs dont, and they often have different side effects.
Tumor Microenvironment As A Unique Challenge For Car T Cells In Pancreatic Cancer
A major obstacle for immunotherapies, in particular CAR T cell therapies, in solid tumors is the immunosuppressive tumor microenvironment . The TME impacts on the efficacy of CAR T cells both by limiting their infiltration and suppressing their function within the tumor .
Another strategy for enhancing CAR T cell efficacy in solid tumors is blocking the inhibitory signals received by the T cells from immunosuppressive populations in the TME. Checkpoint inhibitors, against molecules such as PD-1, CTLA4, TIM-3, and LAG-3 have shown promise as single agents in a number of cancer types but unfortunately, none of these treatment as a single therapy has generated significant clinical benefit in pancreatic cancers. CAR T cells can express high amounts of these checkpoint molecules, which can lead to apoptosis and hypo-function. Results from preclinical studies clearly demonstrated that CAR T cell treatments could benefit from the addition of checkpoint inhibitors . Some early clinical data also support the use of a combination of the checkpoint inhibitors with CAR T cell therapy in treating difficult cancers. A study carried out by Chong et al. reported that in a diffuse large B cell lymphoma patient refractory to CART19, after PD-1 blockade, the patient had an expansion of the CAR T cells and clinically significant antitumor response .
Novel Treatment Targeting Kras G12d Expression Induces Deep And Durable Response
byMike Bassett, Staff Writer, MedPage Today June 1, 2022
A novel T-cell receptor gene therapy may be effective in treating patients with pancreatic cancer and other cancers that express the KRAS G12D mutation, researchers have found.
Their case study — published in the New England Journal of Medicine — showed that a heavily pretreated patient with pancreatic ductal adenocarcinoma achieved a deep and durable response when treated with an infusion of autologous T cells transduced with two TCRs directed against mutant KRAS G12D expression, reported Rom Leidner, MD, of Providence Cancer Center in Portland, Oregon, and colleagues.
Specifically, regression of the patient’s metastatic lung lesions were observed 1 month after cell infusion, with an overall objective partial response of 62% . That response was ongoing at 6 months, with an overall partial response of 72%.
In an editorial accompanying the study, Cornelis J.M. Melief, MD, PhD, of Leiden University Medical Center in The Netherlands, noted that pancreatic ductal adenocarcinoma is the deadliest of all common cancers for a variety of reasons, including the advanced cancer stage at the time symptoms become apparent, the occult presence of micrometastases in the liver and elsewhere at the time of surgery, and its resistance to chemotherapy and immunotherapy.
Thus, the results reported in the study “are remarkable because it shows deep and durable tumor shrinkage in a heavily pretreated patient,” Melief wrote.
Prostate Stem Cell Antigen
Prostate stem cell antigen is a glycosylphosphatidylinositol-anchored cell surface protein involved in intracellular signaling, although much of its function remains unclear. PSCA is expressed in the epithelial cells including that of prostate, kidney, skin, stomach, urinary bladder, esophagus and placenta, and also expressed in differentiating cells such as the ones of prostate and gastric epithelial cells. PSCA has also been detected in several cancer types including prostate, urinary bladder and pancreatic cancers . Aberrant overexpression of PSCA is detected in nearly 60% of the primary PDACs, while the gene expression is not detected in normal pancreatic duct . Therefore, PSCA has been proposed as a specific biomarker for PDAC patients and a promising target for CAR T cell therapies in treating PDAC. An advantage of targeting PSCA is that it is upregulated in pancreatic cancer cells from early stages of malignant transformation , including premalignant pancreatic intraepithelial neoplasias. PSCA may therefore serve as a useful target of immunotherapy that could eliminate malignant cells at all stages of PDAC.
A Phase Ib Study Of Car T
Full Title
Purpose
CAR T-cell therapy is a type of cellular therapy that involves using a patients own T cells , genetically modifying them in the laboratory to recognize a protein on cancer cells, and multiplying them. The modified T cells, known as chimeric antigen receptor T cells, are then returned to the patient to find and kill cancerous cells throughout the body.
In this study, researchers are seeking to find the best dose of a CAR T-cell therapy called CT041 that can be given safely in people with advanced gastric cancer or pancreatic cancer that contains a protein called CLDN18.2. CT041 is designed to attack cancer cells containing this protein. To determine if a patients cancer cells have the CLDN18.2 protein, cancer cells from a previous biopsy or surgery must first be tested during the screening phase of this study.
CT041 is given intravenously during a hospital stay of at least 1 week. For 4 weeks after leaving the hospital, patients must reside within one hour of Memorial Sloan Kettering Cancer Center in case there are any side effects that require medical attention.
Eligibility
To be eligible for this study, patients must meet several requirements, including:
For more information about this study and to ask about eligibility, please contact the office of Dr. Geoffrey Ku at .
Protocol