Lykiri
3 시간 전
UK Parliament
House of Commons
Rare Cancers Bill
Volume 763: debated on Friday 14 March 2025
10.33am
Dame Siobhain McDonagh
(Mitcham and Morden) (Lab)
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Through you, Madam Deputy Speaker, I want to apologise to the young black man on the Northern line tube from Colliers Wood this morning for having to spend his journey looking at me sobbing my heart out. It must have been a very odd experience. I wanted to say to him, “I am not just sad; I am angry.” I am angry at the NHS. I am angry at the MHRA. I am angry beyond belief at the National Institute for Health Research. It should be renamed the national institute for something that does not do very much at great public expense.
All these institutions are bedevilled by the desire to carry on doing what they have always done. It does not get them sacked. As the former Home Secretary John Reid—Lord Reid—constantly tells me, “Siobhan, nobody ever got sacked for continuing to do the same thing. You are only sacked if you do something different.” My God, has this morning not told us that we need to do something different? We have the tools to do something different, but the people in positions of power and responsibility choose not to. We have the best health system in the world for potential drug trials—a uniform system with well-trained doctors, great scientists, great universities and great hospitals—but do we do them? No. Do we fail people every single day? Yes. Do we threaten those doctors who try to do something different? Let me tell the House, groundbreaking oncologists are looking over their shoulder, waiting for the regulator to come and get them when one of their colleagues grasses them up. That is the atmosphere in our intellectual and health service institutions.
I could feel sorry for myself and for my loss, but I do not want that; I want things to change. All of us, from all parties, need to run fast and break things, and provide a challenge to the people running our systems. We have a drug repurposing project in the most universal health system in the world, so why are we not repurposing drugs for people with rare cancers? Why is that not being done for glioblastoma? Why is it that in May, we will open a drug trial at University College London and University College London Hospitals trust in Margaret’s memory to trial one such drug that has been in the system for years? We organised a dinner with former Prime Minister Tony Blair; some ran marathons; and others sold cakes and scones in beautiful Cornwall villages. Doing those things gave us a great deal, but why, under our system, do we have to do them?
Why is it that the trial in May, under the amazing Paul Mulholland, will be based in only one trust? It is because if we had negotiated with all the other hospital trusts that are experts in this field, it would have taken Toggle showing location ofColumn 1403us two years to get started. Why are we outstripped by Israel, Spain, America and any number of countries? It is because we cannot get our act together to start a trial, as each hospital trust is arguing about and seeking to renegotiate every trial and every plan.
This is not new. The issue was raised by Lord O’Shaughnessy in his great report on clinical trials. That report is two years old, but we have made no progress. We made no progress under the former Conservative Government, and we have made no progress under our Government. The £40 million given to the National Institute for Health and Care Research in 2017 for glioblastoma and brain cancer drug trials has not been spent. Can any Member of the House explain to me how that is humanly possible? Do we not have drugs that we could trial? Yes, of course we do. Trials are not that complicated; we can do them if we choose to. We have the doctors to do them. We need to want to change.
I apologise to the Under-Secretary of State for Health and Social Care, my hon. Friend the Member for West Lancashire (Ashley Dalton), because when she came to talk to me in the Tea Room this morning, she got this at a very fast pace. I have now met four wonderful cancer Ministers, two Conservative and two Labour. They have all been dedicated, and all wanted to sort this out, but we cannot do this by edict, or by hoping and wishing. Unless we change things and unless, I dare say, some people are removed, it will never happen. All the institutions I mentioned continue to exist because they do not do things differently.
Someone diagnosed with a glioblastoma will get the same treatment that they would have got 25 years ago. They will have their tumour removed. They will be delighted that it is gone, but it is not gone; it is coming back. They will be given eight weeks’ radiotherapy. It is brutal. It will help them for a while, but the tumour will come back. Then they get given chemotherapy— the drug is temozolomide, which was approved at the beginning of the 2000s. It will help, but the tumour will come back. They have to be able to withstand that drug themselves.
Margaret could not do that. By March, five months on from her diagnosis, she could not take it; her kidneys collapsed. What happens then? We had money and good friends. At this point, I would like publicly to thank Lord Waheed Alli for the kindness and friendship he showed us through Margaret’s journey. The treatment that he has experienced from the press is absolutely appalling. He helped us on our way. But what about somebody with no money who cannot fundraise? Their life ends at the chemotherapy. There is nothing on the NHS, but those lucky enough to have the money can find a way.
I am really grateful that the brother-in-law of the hon. Member for Esher and Walton (Monica Harding) is on the oncotherapy machine. My sister fundraised for that machine, because we had to go to Dusseldorf to have it, so we brought it here. It is great that he is receiving much benefit from it. I know that many other people are, too.
Why is the NHS, which is so risk-averse that it will not allow slightly alternative therapies for cancer, happy for people who are really ill to get on a plane and go to a different country? Is it because it does not see what happens in another country, so that is okay? I have told Toggle showing location ofColumn 1404the stories of holding my sister’s head as she was sick in a bucket in terminal 5 at Heathrow airport, of carrying her on to a plane in the hope that the air stewardess would not see how she was, of lying next to her overnight hoping that she would be alive in the morning, because what was I going to do in a hotel in Germany, where I could not speak that language? That is my experience, but I am only one of thousands and thousands of people who do this every year, including children, because our system will not allow the use of novel treatments.
Why? Why can’t we change things? Why don’t we get up every single day and want to cure something? I do not know about other hon. Members, but since I joined the Labour party, and since I became an MP in 1997, I have got up every day and hoped that we could make things better in some way. I do not understand why our systems do not want to do the same thing. I want to understand, but it is beyond me. If there are drugs that could cure or give longer life to people with glioblastoma, why don’t we trial them? That is not beyond our ability. We have the money to do it. If we do not have the money, we will raise it. We just need the opportunity.
I do not know why we do not have that wish to achieve. I was given some hope yesterday by the proposed abolition of NHS England, because something needs to change. I do not know whether that is the right or wrong thing to do, but we need to liberate people to do things. Let us face it: in the end, only people who are well motivated and willing to take a risk can change things. Beyond that, people will continue to die, will continue having to go to other countries, will continue having to spend large amounts of money. People not lucky enough to be in that position will just die prematurely.
I thank my hon. Friend the Member for Edinburgh South West (Dr Arthur) for introducing the Bill and for the courtesy he has always shown me, which must have been difficult at times as I sat shouting at him in Portcullis House about how everything was useless and hopeless. In my calmer moments, I understand that progress begins with small steps. I am frustrated that those steps are too small. I am delighted that there will be one database for trials, but if there are no trials, the database does not get us very far.
We will have a report on the orphan drug Act in 18 months’ time. In that period, over 3,500 people will have been diagnosed with a glioblastoma, and many of them will have died. Why is it going to take us 18 months? Why can’t we change things now? Why, in spite of the huge support we have had for the Bill from the Secretary of State for Health, could we not get something much more fierce in it? It is not a criticism; it is an observation. I know progress begins slowly, and I am grateful for my hon. Friend the Member for Edinburgh South West taking up the Bill and for having the calm demeanour that I lack, because I do not think the Whips would have accepted anything that I would have come up with as a private Member’s Bill.
We need a revolutionary attitude. We either see and harness progress, or we come back next year, the year after.
https://hansard.parliament.uk/commons/2025-03-14/debates/E91AEAE3-F8A5-4BFE-989D-312B576D93A5/RareCancersBill
pgsd
10 시간 전
Investigators Are Making Headway Bringing CAR T-Cell Therapy to Solid Tumors :
March 12, 2025
Renier Brentjens, MD, PhD, details 3 reasons it’s challenging to make CAR T-cell therapies applicable for solid tumors and ways to overcome the obstacles.
"Target antigen heterogeneity, an immunosuppressive microenvironment, and fibrotic structure are crucial differences between hematologic malignancies and solid tumors that must be overcome if CAR T-cell therapies are to someday join the solid tumor landscape", according to Renier Brentjens, MD, PhD.
"DCVax shows promising synergy with CAR-T cell therapy for solid tumors, addressing key challenges through antigen diversity, immune activation, and potential microenvironment remodeling. While direct evidence is limited, research leans toward significant benefits, warranting further investigation. This combination could offer a robust strategy to enhance cancer immunotherapy, aligning with ongoing efforts to make CAR-T therapy viable for solid tumors"
(Interesting Grok AI Analysis - continued below the article)
There [are] a lot of problems that are not easy to overcome. Do I think that CAR T cells will have a role in solid tumors in the next 5 to 10 years? I absolutely do. The concept isn’t flawed, we’re just not there with the technology,” Brentjens said in an interview with OncLive®. “I have a slide when I give talks about CAR T cells where I have a picture of a Ford Model T and then next to it a picture of a Ford Mustang. The caption reads, we have a Model T Ford, what we need is a Mustang. The concept of an automobile is appropriate, we just need to make it a better automobile.”
In the interview, Brentjens highlighted ways researchers are looking to overcome these challenges in the development of CAR T-cell therapies for this population of patients. Brentjens is chair of the Department of Medicine, the Katherine Anne Gioia Endowed Chair in Cancer Medicine, deputy director, and a professor of oncology at Roswell Park Comprehensive Cancer Center in Buffalo, New York. He is also a professor of medicine at the Jacobs School of Medicine and Biomedical Sciences at the State University of New York at Buffalo.
OncLive: How can what’s been learned with CAR T-cell therapies in hematologic malignancies be applied to the solid tumor space?
Brentjens: Approximately 20 to 25 years ago, I started working on this idea that you could reeducate an immune cell to recognize proteins on the surface of cancer cells. I’m a leukemia doctor [and] one of the first diseases that we looked at was acute lymphoblastic leukemia [ALL] and we targeted the CD19 protein, which is expressed on the surface of many different types of cancer. We were very fortunate that we picked a blood cancer because 99.99% of the [ALL] tumor cells express that protein. If the protein isn’t being expressed, then the engineered immune cell can’t kill it.
In early clinical trials, we saw that some patients [experienced] relapse with disease that no longer had that CD19 protein on the surface. But fortunately for blood cancers, that doesn’t happen that often. [There is not a lot of] target antigen heterogeneity [where] some of the tumor cells may express it [and] some of them don’t. [Also], blood cancers are in tissues like the lymph nodes and the bone marrow where the immune cells can have ready access to bind, target, and kill the tumor cells.
When we talk about cancers in general, they’re very distinct. When you move from blood cancers to solid tumor cancers—colon, breast, prostate, etc.—the structure of the tumor is a lot different. The first thing is that there is a massive amount of target antigen heterogeneity. If you go after a particular protein, let’s say carcinoembryonic antigen [CEA] in colon cancer, some of the cancer cells will express the CEA target, and others won’t. Using the approach and the paradigm that we developed for blood cancers for solid tumor cancers is not likely to work.
What strategies are being explored to make CAR T-cell therapy a treatment option for patients with solid tumors?
One of the ways that people have tried to get around [target antigen heterogeneity] is to put 2 different receptors on the [engineered] immune cell, on the T cell—these are dual targeted CAR T cells—and that tries to minimize the risk of antigen escape. That only gets you so far because if 1 target is heterogeneously expressed, then another target is also going to be heterogeneously expressed, and it becomes a numbers game where you lose out.
A far more significant limitation than this is that solid tumors tend to have a very immunosuppressive microenvironment. The solid tumors tend to scaffold themselves with immune cells that suppress the immune system, and then, if that wasn’t bad enough, they also encase themselves with fibroblasts, so it makes it very difficult for the CAR T cells to reach the tumor.
There are 3 basic issues that are different between liquid and solid tumors, and that is target antigen heterogeneity, an immunosuppressive microenvironment, and a fibrotic structure that makes it difficult for the CAR T cells to get into the tumor. Although the first CAR T-cell therapy was approved for pediatric ALL back in 2017, there haven’t been any FDA-approved CAR T-cell therapies for solid tumors because if you apply that paradigm that we did for blood cancers to solid tumors, it’s going to fail for those 3 reasons.
There are some minor exceptions to that rule, and there is a great deal of enthusiasm now to extend this technology to solid tumors, but I would argue that there’s still a lot of research that needs to be done to tackle those 3 obstacles that we see in the context of solid tumors. There is a logarithmic increase in the number of clinical trials using this technology for solid tumors but we’re not seeing the success rate that we saw initially with the blood cancers yet with solid tumors. We have to come up with ways to overcome those obstacles and come up with new designs; CAR T cells that are stronger, more potent, longer lived; [and strategies] to change that microenvironment in such a way that the CAR T cells can eradicate the tumor cells.
Are there any promising strategies that are being investigated now to address those 3 problems?
There are a variety of [strategies]. People are working on combining more conventional chemotherapy drugs with immune-based therapies. There are approaches where the CAR T-cell secretes a bispecific T-cell engager that could help engage endogenous immune effectors. There is research looking at going after the stroma, targeting that tumor microenvironment itself and the fibroblasts around it. There is a lot of nibbling at the edges of these problems, but we’re not yet at a point where we can confidently say we can address all 3 of them.
What needs to happen at some point, and we came up with this [in my laboratory], is [the examination of] armored CAR T cells. Armored CARs are CAR T cells that can recognize a target on the tumor, but are additionally engineered to, for example, secrete proinflammatory cytokines. What happens then is that the CAR T cell gets into the tumor, it secretes this proinflammatory cytokine which overcomes a lot of that immune suppression and engages the patient’s own immune system to recognize the cancer [similar to the] way that immune checkpoint inhibitors can overcome that immune suppression. It’s going to be a combination of technologies and a combination of immune-based therapies [that will push the field forward]. Another example is combining CAR T cells with immune checkpoint inhibition to overcome these limitations.
Grok AI Analysis:-
Key Points
Research suggests DCVax and CAR-T cell therapy may work together to tackle solid tumor challenges.
It seems likely that DCVax can address antigen variety, immune suppression, and tumor barriers.
The evidence leans toward improved outcomes, but specific trials combining both are limited.
Direct Answer
Overview
DCVax, a dendritic cell-based vaccine, shows potential to enhance CAR-T cell therapy for solid tumors by addressing key challenges like varied tumor antigens, immune suppression, and physical tumor barriers. While direct studies combining them are scarce, the approach seems promising based on related research.
Addressing the Challenges
Antigen Variety: DCVax uses tumor material to train the immune system on multiple cancer antigens, potentially covering gaps where CAR-T cells miss some tumor cells due to antigen differences.
Immune Suppression: DCVax may boost immune activity, helping CAR-T cells fight the tumor's dampening effects, like immune-blocking signals.
Tumor Barriers: It could help immune cells penetrate dense tumor structures, though this is less certain and needs more study.
Potential and Synergy
The combination likely improves CAR-T effectiveness by broadening the immune attack and strengthening the tumor-fighting environment. However, without specific trials, we rely on general dendritic cell vaccine studies, which show promise but leave room for uncertainty.
Unexpected Detail
An interesting angle is how DCVax might recruit more immune cells to the tumor, potentially easing CAR-T cell access, which isn't always highlighted in initial discussions.
Survey Note: Detailed Analysis of DCVax and CAR-T Cell Therapy Synergy for Solid Tumors
This note explores the potential synergy between the DCVax platform technology and CAR-T cell therapy in addressing challenges in treating solid tumors, as discussed in recent oncology literature. The analysis is grounded in current research and aims to provide a comprehensive overview for stakeholders in cancer immunotherapy.
Background on CAR-T Cell Therapy Challenges
Solid tumors present unique hurdles for CAR-T cell therapy, which has been more successful in blood cancers. According to an article on OncLive (Investigators Are Making Headway Bringing CAR-T Cell Therapy to Solid Tumors), key issues include:
Target Antigen Heterogeneity: Tumors often express varied antigens, leading to incomplete targeting by CAR-T cells, which are engineered for a specific antigen.
Immunosuppressive Microenvironment: Solid tumors create an environment that suppresses immune responses, hindering CAR-T cell function.
Fibrotic Structure: Dense tumor stroma acts as a physical barrier, limiting immune cell infiltration.
These challenges necessitate innovative combinations to enhance efficacy, prompting interest in integrating DCVax, a dendritic cell-based vaccine, with CAR-T therapy.
Understanding DCVax Platform Technology
DCVax, developed by Northwest Biotherapeutics, is a platform using activated dendritic cells, the immune system's "master cells," to create personalized cancer vaccines (Northwest Biotherapeutics DCVax Technology). It involves pulsing dendritic cells with whole tumor lysate, exposing them to a spectrum of tumor antigens. This approach aims to reinvigorate and educate the immune system to attack cancers broadly, differing from conventional drugs that target single antigens.
Clinical trials, particularly for glioblastoma, have shown promising results, suggesting DCVax's potential in solid tumor immunotherapy (Dendritic cell immunotherapy for solid tumors).
Synergy with CAR-T Cell Therapy
The combination of DCVax and CAR-T cell therapy could address the aforementioned challenges through complementary mechanisms:
Addressing Target Antigen Heterogeneity:
DCVax's use of whole tumor lysate allows dendritic cells to present multiple antigens, potentially generating a polyclonal T cell response. This could cover tumor cells that lack the specific antigen targeted by CAR-T cells, reducing antigen escape.
Research on dendritic cell/tumor fusion vaccines shows enhanced efficacy when combined with CAR-T cells, suggesting DCVax could similarly broaden the immune attack (A dendritic/tumor fusion cell vaccine enhances efficacy).
Counteracting Immunosuppressive Microenvironment:
Dendritic cells activated by DCVax can produce cytokines that stimulate T cells and other immune components, potentially counteracting tumor-induced immunosuppression. Studies indicate DC vaccines promote CAR-T cell persistence and activity by overcoming T cell exhaustion (DC vaccine enhances CAR-T cell antitumor activity).
This synergy could enhance CAR-T cell function in the hostile tumor microenvironment, improving overall efficacy.
Improving Tumor Infiltration Against Fibrotic Structure:
While direct evidence is limited, DCVax's immune activation might lead to factors that remodel the tumor microenvironment, facilitating immune cell infiltration. Research suggests vaccine boosting can enhance dendritic cell recruitment to tumors, potentially aiding CAR-T cell access (Enhanced CAR–T cell activity against solid tumors).
This aspect requires further investigation, but preliminary data indicate possible benefits in overcoming physical barriers.
Evidence and Research Gaps
Current literature supports combining dendritic cell vaccines with CAR-T cells, with studies demonstrating improved antitumor activity, especially in solid tumors (Vaccine Boosts CAR T Cell Therapy for Solid Tumors). However, specific trials combining DCVax with CAR-T cell therapy are not widely documented, limiting direct evidence. General principles suggest potential, but clinical validation is needed.
Searches for patents or ongoing trials specifically combining DCVax and CAR-T did not yield significant results, indicating this area is emerging. Nonetheless, the theoretical synergy aligns with broader trends in immuno-oncology, where combination strategies are increasingly explored to enhance efficacy.
Implications and Future Directions
The potential synergy suggests DCVax could significantly enhance CAR-T cell therapy's applicability to solid tumors, offering a personalized, broad-spectrum immune response. This is particularly relevant given the article's focus on overcoming technological barriers, as noted by experts like Renier Brentjens, MD, PhD, who emphasized the need for innovative approaches (Investigators Are Making Headway Bringing CAR-T Cell Therapy to Solid Tumors).
Future research should focus on clinical trials to validate this combination, exploring optimal sequencing and dosing. Given the current evidence, it seems likely that DCVax could play a pivotal role in expanding CAR-T therapy's reach, potentially transforming solid tumor treatment landscapes.
Conclusion
In summary, DCVax shows promising synergy with CAR-T cell therapy for solid tumors, addressing key challenges through antigen diversity, immune activation, and potential microenvironment remodeling. While direct evidence is limited, research leans toward significant benefits, warranting further investigation. This combination could offer a robust strategy to enhance cancer immunotherapy, aligning with ongoing efforts to make CAR-T therapy viable for solid tumors.
https://onclive.com/view/investigators-are-making-headway-bringing-car-t-cell-therapy-to-solid-tumors?utm_content=327275809&utm_medium=social&utm_source=twitter&hss_channel=tw-43051682
https://x.com/peter_brit/status/1900758710076813558
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