This week American movie icon Richard Roundtree, who played one of the first Black action heroes in the blaxploitation ’70s era of film, died in his home in Los Angeles at 81 years of age due to pancreatic cancer. Roundtree starred in the 1971 “Shaft” film series that depicted his iconic character “John Shaft”, a private detective with a brown leather jacket with a turned-up collar and a dark mustache. He is one of the latest celebrities to die from pancreatic cancer, but he has not been the only one. With him many movie directors, talented actors to politicians, business and industry leaders, legal professionals, as well as the rich and poor and everyone in between, have died as a result of pancreatic cancer – a disease that doesn’t discriminate. Hence, the list of well know people, who have died as the result of pancreatic cancer, is long – very long and includes celebrities like:
- Alex Trebek, the host of the long-running game show Jeopardy, who passed away from complications of the disease at his home on November 8, 2020;
- Ruth Bader Ginsburg, the Supreme Court justice died due to complications of pancreatic cancer on Sept. 18, 2020, and became the first woman to lie in state at the U.S. Capitol;
- John Hurt, the celebrated English actor known for his roles in the Harry Potter movies, Alien, and The Elephant Man, passed away in January 2017 at age 77;
- Luciano Pavarotti, the bearded tenor who sang at the world’s greatest opera houses and classical music halls, but also joined James Brown, Bono, the Spice Girls, and many other pop and rock stars, passed away from complications of pancreatic cancer on September 6, 2007, at age 71;
- Patrick Swayze, who payed in The Outsiders, a movie directed by Francis Ford Coppola and famously played Jennifer Grey’s dance teacher in the 1987 classic Dirty Dancing, died of pancreatic cancer in 2009 at age 57.
- William Garson Paszamant, a noted actor of stage, film, and television, died at age 57 at his home in Los Angeles as the result of pancreatic cancer. He was perhaps best known for his role in the iconic HBO television series, Sex and The City.
- Eiko Ishioka, was the celebrated costume designer on Francis Ford Coppola’s 1992 film Bram Stoker’s Dracula, which earned her an Academy Award for Best Costume Design. Ishioka was also known as the designer of the 2002 Winter Olympics uniforms and outerwear for the members of the Swiss, Canadian, Japanese and Spanish teams and as the director of costume design for the opening ceremony of the 2008 Summer Olympics in Beijing, China;
- Henry Mancini, who was, without a doubt, one of the greatest film composers in history and was nominated for 18 Academy Awards throughout his career, and took home four Oscars for his work in the classic film, Breakfast at Tiffany’s (Best Original Song for “Moon River” and Best Scoring of a Dramatic of Comedy Picture) as well as Best Original Song in 1962 for Days of Wine and Roses (from the movie with the same title), and finally, for Best Original Score for the 1982 film, Victor/Victoria (directed by Blake Edwards), died from complications due to pancreatic cancer in 1994, less than four months after diagnosis.
These are just a few of the many people on the long list of those who have died due to (complications) after being diagnosed with pancreatic cancer.
A leading cause of cancer
Today, pancreatic cancer remains the fourth leading cause of cancer-related death in the world, and scientists believe that the disease will ultimately become the number two cause of cancer-related deaths. [1] Clinically, pancreatic cancer is the general term for a malignant tumor formed in the epithelial cells of glandular structures in the pancreatic ductal cells, which is referred to as adenocarcinoma [1], and pancreatic ductal adenocarcinoma (PDAC).
PDAC, which accounts for more than 90% of pancreatic cancers [2], is a clinically challenging cancer. This is, in part, due to both its late stage at diagnosis and its resistance to available chemotherapy. In most cases, the disease is diagnosed after it metastasized. At this point, surgery cannot cure it, which means the general outlook is poor. The disease remains a fatal malignancy of both the digestive system and endocrine system with disappointing prognoses. Following diagnosis, the 5-year survival rate of 6% following a diagnosis.[3]
Worldwide, the number of newly diagnosed PDAC cases is approaching five million new patients each year. As the seventh leading cause of cancer-related deaths, PDAC also accounts for more than 4.6 million new deaths. Although much of this increase of the incidence of pancreatic cancer is due to ageing worldwide populations, there are key modifiable risk factors for pancreatic cancer such as cigarette smoking, obesity, diabetes and alcohol intake. [4]
Resilient to chemotherapy
The presence of a dense stroma makes this form of cancer resilient to chemotherapy, with very few potent inhibitors like nanoparticle albumin-bound paclitaxel (nab-paclitaxel; Abraxane®; Bristol-Myers Squibb Company/BMS) that can work in combination with chemotherapeutic agents.
Due to the poor survival outcomes, PDAC is the seventh leading cause of global cancer death despite being the 10th most common cancer[5]. And Given the increase in the incidence of PDAC, it is estimated that PDAC will surpass breast cancer as the third leading cause of cancer death by 2025.
Standard of care
Effective treatment options remains limited for patients diagnosed with PDAC. These treatment options generally focus on conventional chemotherapeutic regimens (e.g., gemcitabine (Gemzar®; Eli Lilly & Co), oxaliplatin (Eloxatin; Sanofi), and FORLFIRINOX*) and, if possible, on curative-intent surgical resection. However, due to the fact that the disease is often diagnosed in a late stage, when the cancer has metastasized, the majority of patients are no longer eligible by the time the disease is detected. As a result, overall outcomes are disappointing, with a 5-year survival rate of 6%. [6] The few choices of therapeutic options with limited effects, the advanced stage at presentation due to late detection, and the vicious behavior of PDAC contribute to the high mortality rate. Therefore, developing novel therapies for PDAC are direly needed.
A recently published open access research article discussing the effect of chimeric antigen receptor (CAR) T-cells therapy against protease-activated receptor 1 (PAR1) for treating pancreatic cancer, published online in BMC Medicine, addressed the current state of some cutting edge research for effective therapies. [7]
CAR T-cell therapy
Despite improvements in multimodality therapy, overall, PDAC has a unfavorable prognoses and additional novel therapeutic targets and candidate molecules to escalate the treatment response are urgently needed. [8]
Immunotherapies like CAR T-cell therapy have, for example, transformed the care of relapsed and refractory aggressive B-cell lymphoma, and improved outlooks in for patients in a number of other cancer types. But the majority of these disease are hematological malignancies, and have had only limited efficacy in this disease setting.
Researchers agree that there are major barriers to applying a CAR T-cell therapy strategy for the treatment of PDAC. These barriers including a lack of specific cancer-associated antigen expressions, complex logistics, an immune-suppressive TME, toxicity concerns, and manufacturing/financial restrictions. [7]
Patient access
Patient access to novel CAR T-cell therapies may be limited by the available manufacturing technology and capacity. [9]. In addition, manufacturing time may also limit access. For example, patients generally have to wait for a ‘manufacturing slot,’ an allocated date when the manufacturing facility can receive the patient’s autologous apheresis product to start manufacturing CAR T-cells. This time it takes to develop a final product, frequently ranges from 2 to 4 weeks. This prolonged ‘waiting’ time for patients who often have been diagnosed with aggressive disease, may requires prompt treatment in the form of bridging therapy for disease stabilization while their CAR T-cells therapy is manufactured. Being heavily pre-treated, these patients often may decline clinically and become ineligible while waiting to receive treatment. [10]
In the treatment of PDAC, past trials of CAR T-cell therapy have not always been very successful. The results from published studies demonstrate that only a limited subset of participating patients achieved stable disease, but most patients only had short-term responses or disease progression.
But investigators hope that new targets and new studies will result in effective, novel treatment options.
In one study, researchers developed a CAR T-cell therapy approach designed to target PAR1 using a human anti-PAR1 scFv antibody fused to the transmembrane region with two co-stimulatory intracellular signaling domains of cluster of differentiation 28 (CD28) and CD137 (4-1BB), added to CD3ζ in tandem.[7]
In this study, engineered PAR1CAR T-cells eliminated PAR1 overexpression and transforming growth factor (TGF)-β-mediated PAR1-upregulated cancer cells by approximately 80% in vitro. The adoptive transfer of PAR1CAR-T cells was persistently enhanced and induced the specific regression of established MIA PaCa-2 cancer cells by > 80% in xenograft models. [7]
Accordingly, proinflammatory cytokines/chemokines increased in CAR T-cell-treated mouse sera, whereas Ki67 expression in tumors decreased. Furthermore, the targeted elimination of PAR1-expressing tumors reduced matrix metalloproteinase 1 (MMP1) levels, suggesting that the blocking of the PAR1/MMP1 pathway constitutes a new therapeutic option for PDAC treatment.[7]
The investigators in this study moted that PAR1 overexpression was found to be closely associated with tumor progression and poor survival outcomes in PDAC. Rather than being specific to tumor cells, PAR1 is expressed by the surrounding stroma that consists of endothelial cells, fibroblasts, and macrophages.
The study outcomes demonstrated that activation of stromal cell-associated PAR1 expression in the TME leads to increased vascular permeability, ECM production, and cytokine secretion, thereby promoting tumorigenesis. In this study, we developed PAR1-targeted CAR T-cells using third-generation CARs containing additional signaling domains, including CD28, CD137 (4-1BB), and CD247, to augment activation of cytokine production and a tumor-eradication ability.
PAR1-targeted CAR T-cells further demonstrated specific killing potency both in vitro and in a xenograft murine model, accompanied by cytokine release. The investigator’s analyses revealed that the cytotoxic activity of PAR1CAR T-cells toward PDAC cells was significantly correlated with the targeting specificity. Furthermore, their cell line xenograft murine model, compared to mice treated with mock-transduced T cells, non-transduced CD3+ T cells, or 1 × PBS, PAR1CAR-T-cell-treated mice had significantly greater TME infiltration, cytokine and chemokine induction, and tumor-eliminating effects.
The engineered CAR T-cell affinity and efficacy were affected by the PAR1 antigen density on target cells in PDAC cell lines and the xenograft animal model. In this study, the investigators not only examined the influence of CAR affinity and antigen density on primary T-cell activation but also its cytotoxic ability in vivo.
Based on the available study data, the investigators concluded that this is a highly promising beginning, suggesting the potential of future applications of PAR1-targeted CAR-T-cell-based immunotherapy to human PDAC.
Overall, the expectation is that the number of CAR T-cell therapies are expected to grow exponentially, but, at the same time, this growth will likely exacerbate two major current limitations of this type therapy strategy: patient access and financial burden to the (global) healthcare system.
Other approaches
During the annual meeting of the European Society for Medical Oncology (ESMO 2023), held from October 20 – 24, 2023 in Madrid, Spain, Oncolytics Biotech presented positive updated data from the GOBLET (Gastrointestinal tumOrs exploring the treatment comBinations with the oncolytic reovirus peLarEorep and anTi-PD-L1) study, a phase 1/2 multiple indication study in advanced or metastatic gastrointestinal tumors.
The study is being conducted at 12 centers in Germany and managed by AIO-Studien-gGmbH, includes co-primary endpoints of objective response rate (ORR) assessed at week 16 and safety.
Key secondary and exploratory endpoints include additional efficacy assessments and evaluation of potential biomarkers (T-cell clonality and CEACAM6). The study employs a Simon two-stage design with Stage 1 comprising four treatment groups expected to enroll a total of approximately 55 patients.
The data, included in a poster, demonstrated positive, updated results from the Phase 1/2 GOBLET study evaluating pelareorep**-based combination therapy in patients with pancreatic ductal adenocarcinoma (PDAC),
“We are very pleased to share such positive and consistent data on pelareorep from the PDAC arm of the GOBLET study, including an impressive overall response rate, 7.2 months of median progression-free survival, interim median overall survival of 10.6 months, and expansion of both pre-existing and new T-cell clones. These data build upon results from previous studies showing the clinical benefit of pelareorep combination therapy in PDAC and support the decision to move to a licensure-enabling study in pancreatic cancer,” noted Dr. Matt Coffey, MD, President and Chief Executive Officer of Oncolytics.
“Everything we do … is focused on advancing the development of our immunotherapy candidate, pelareorep, with a goal of providing improved care and longer survival for patients with pancreatic cancer and other tumor types. The data we are presenting at ESMO provide a solid foundation as we advance our pancreatic cancer program through the Precision PromiseSM Phase 3 trial in this indication,” Coffey added.
Other recent developments in include:
- The development of onvansertib monotherapy and combination therapy in the treatment of metastatic pancreatic ductal adenocarcinoma (mPDAC) as plans for a mPDAC first-line investigator-initiated trial (IIT) of the combination of onvansertib plus standard-of-care (SoC). Onvansertib effectively targets PLK1, an enzyme that is over-expressed in many cancer types. PLK1 is hijacked by tumor cells allowing uncontrolled growth in the M phase of the cell cycle. PLK1 is also involved in the repair of damaged DNA in the S phase of the cell cycle. With chemotherapies and targeted cancer drugs damage DNA, onvansertib inhibits PLK1’s ability to repair DNA damage and increases the efficacy of the standard of care therapy in a variety of indications.
“We are excited that the data released from these trials, in two challenging cancers with low survival rates, expands the opportunity for onvansertib beyond our lead program in RAS-mutated mCRC,” explained Mark Erlander, Ph.D., Chief Executive Officer of Cardiff Oncology.
“In pancreatic cancer, the strength of the data provides a clear rationale for a first-line trial using onvansertib in combination with standard of care, which we believe provides the greatest opportunity for a positive impact on patients. In small cell lung cancer, we are encouraged to observe single-agent activity with onvansertib monotherapy in this difficult-to-treat extensive stage refractory setting,” Erlander concluded.
Note: * FOLFIRINOX is a chemotherapy combination which contains the drugs leucovorin calcium (folinic acid), fluorouracil, irinotecan hydrochloride, and oxaliplatin.
** Pelareorep an oncolytic virus previously known under the trademark Reolysin, is a proprietary isolate of the unmodified human reovirus being developed as a systemically administered immuno-oncological viral agent for the treatment of solid tumors and hematological malignancies.
Reference
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[2] Jin C, Bai L. Pancreatic cancer–current situation and challenges. Gastroenterol Hepatol Lett . 2020;2:1–3.
[3] Wood LD, Canto MI, Jaffee EM, Simeone DM. Pancreatic Cancer: Pathogenesis, Screening, Diagnosis, and Treatment. Gastroenterology. 2022 Aug;163(2):386-402.e1. doi: 10.1053/j.gastro.2022.03.056. Epub 2022 Apr 7. PMID: 35398344; PMCID: PMC9516440.
[4] Klein AP. Pancreatic cancer epidemiology: understanding the role of lifestyle and inherited risk factors. Nat Rev Gastroenterol Hepatol. 2021 Jul;18(7):493-502. doi: 10.1038/s41575-021-00457-x. Epub 2021 May 17. PMID: 34002083; PMCID: PMC9265847.
[5] Menini S, Iacobini C, Vitale M, Pesce C, Pugliese G. Diabetes and Pancreatic Cancer-A Dangerous Liaison Relying on Carbonyl Stress. Cancers (Basel). 2021 Jan 16;13(2):313. doi: 10.3390/cancers13020313. PMID: 33467038; PMCID: PMC7830544.
[6] Müller PC, Frey MC, Ruzza CM, Nickel F, Jost C, Gwerder C, Hackert T, Z’graggen K, Kessler U. Neoadjuvant Chemotherapy in Pancreatic Cancer: An Appraisal of the Current High-Level Evidence. Pharmacology. 2021;106(3-4):143-153. doi: 10.1159/000510343. Epub 2020 Sep 23. PMID: 32966993.
[7] Hung HC, Fan MH, Wang D, Miao CH, Su P, Liu CL. Effect of chimeric antigen receptor T cells against protease-activated receptor 1 for treating pancreatic cancer. BMC Med. 2023 Sep 4;21(1):338. doi: 10.1186/s12916-023-03053-9. PMID: 37667257; PMCID: PMC10478223.
[8] Yeo D, Giardina C, Saxena P, Rasko JEJ. The next wave of cellular immunotherapies in pancreatic cancer. Mol Ther Oncolytics. 2022 Feb 1;24:561-576. doi: 10.1016/j.omto.2022.01.010. PMID: 35229033; PMCID: PMC8857655.
[9] Ganeeva I, Zmievskaya E, Valiullina A, Kudriaeva A, Miftakhova R, Rybalov A, Bulatov E. Recent Advances in the Development of Bioreactors for Manufacturing of Adoptive Cell Immunotherapies. Bioengineering (Basel). 2022 Dec 15;9(12):808. doi: 10.3390/bioengineering9120808. PMID: 36551014; PMCID: PMC9774716.
[10] Lutfi F, Holtzman NG, Kansagra AJ, Mustafa Ali M, Bukhari A, Yan J, Samanta S, Gottlieb D, Kim DW, Matsumoto LR, Gahres N, Ruehle K, Lee ST, Law JY, Kocoglu MH, Atanackovic D, Yared JA, Hardy NM, Molitoris J, Mohindra P, Rapoport AP, Dahiya S. The impact of bridging therapy prior to CD19-directed chimeric antigen receptor T-cell therapy in patients with large B-cell lymphoma. Br J Haematol. 2021 Nov;195(3):405-412. doi: 10.1111/bjh.17738. Epub 2021 Sep 9. PMID: 34500492.
Featured image: General images of ESMO 2019 Congress being held in Barcelona, Spain, September 27 – October 1, 2019. Courtesy European Society for Medical Oncology (ESMO). Used with Permission
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