Tag Archives: #bloodcancer

Blood Cancer Patients With COVID-19 Fare Better With Convalescent Plasma (Medicine)

Retrospective study also indicates outcomes of critically ill patients in ICU improve when given antibodies from recovered COVID-19 patients

A large, retrospective, multicenter study involving Washington University School of Medicine in St. Louis indicates that convalescent plasma from recovered COVID-19 patients can dramatically improve likelihood of survival among blood cancer patients hospitalized with the virus.

The therapy involves transfusing plasma — the pale yellow liquid in blood that is rich in antibodies — from people who have recovered from COVID-19 into patients who have leukemia, lymphoma or other blood cancers and are hospitalized with the viral infection. The goal is to accelerate their disease-fighting response. Cancer patients may be at a higher risk of death related to COVID-19 because of their weakened immune systems.

The data, collected as part of a national registry, indicate that patients who received convalescent plasma from donors who had recovered from COVID-19 had a death rate of 13.3% compared with 24.8% for those who did not receive it.

The difference was especially striking among severely ill patients admitted to intensive care units (ICUs). Such patients treated with convalescent plasma had a death rate of 15.8% compared with 46.9% for those who didn’t receive the treatment.

“These results suggest that convalescent plasma may not only help COVID-19 patients with blood cancers whose immune systems are compromised, it may also help patients with other illnesses who have weakened antibody responses to this virus or to the vaccines,” said Jeffrey P. Henderson, MD, PhD, an associate professor of medicine and of molecular microbiology at Washington University. “The data also emphasize the value of an antibody therapy such as convalescent plasma as a virus-directed treatment option for hospitalized COVID-19 patients.”

The research is published June 17 in the journal JAMA Oncology.

Henderson collaborated with researchers from the international COVID-19 & Cancer Consortium (CCC19) formed over a year ago to collect and analyze data on the disease’s unique interactions. More than 70 institutions in the consortium — including Advocate Aurora Health in Wisconsin and Illinois, Vanderbilt University Medical Center in Nashville, Tenn., and the Mayo Clinic in Rochester, Minn. — participated in this study.

The scientists looked back at patient data to compare the 30-day mortality of 966 hospitalized adults with a blood cancer, such as leukemia, lymphoma or multiple myeloma, who also were diagnosed with COVID-19. The patients, whose average age was 67, were hospitalized at some point from March 17, 2020, through Jan. 21, 2021, due to complications from COVID-19.

Of the patients studied, 143 received convalescent plasma, and 823 did not. Of the 338 patients admitted to ICUs because of severe COVID-19 symptoms, such as difficulty breathing or cardiac distress, those who received the treatment were more than twice as likely to survive.

“In March 2020, the Food and Drug Administration provided a pathway for hospitalized patients to receive COVID-19 convalescent plasma if requested by their physicians,” Henderson explained. “After this, the decision to give convalescent plasma was made by physicians and patients on a case-by-case basis. There were no restrictions on when during the course of illness convalescent plasma could be given to patients.”

Early in the pandemic, many scientists urged evaluation of convalescent plasma to treat the virus, based on the plasma’s historical effectiveness in fighting other viruses. During the 1918 Spanish flu pandemic, some newly infected patients were treated successfully with plasma from people who had recovered from the flu. Additionally, during the outbreaks of severe acute respiratory syndrome (SARS) in 2002 and 2003, health-care workers used plasma transfusion experimentally and, in many cases, successfully to treat small numbers of people. SARS is caused by a coronavirus closely related to the one that causes COVID-19.

However, limited data on the novel coronavirus also caused pause among physicians. Randomized controlled trials — the gold standard in research — proved elusive, in most cases, due to the time required to prepare and coordinate adequate trials, and the need for scientists to prioritize among multiple investigational treatment options. Some preliminary results also disappointed, showing convalescent plasma only worked as a treatment in the general patient population if infused within days after diagnosis in patients who hadn’t yet progressed to having severe complications.

“As more COVID-19 patients began receiving convalescent plasma, we started hearing physicians around the country report remarkable clinical improvements following convalescent plasma infusions in COVID-19 patients with blood cancers and antibody deficiencies, some of whom were already very ill,” said Henderson, one of several physicians who formed the COVID-19 Convalescent Plasma Program Leadership Group to study the use of convalescent plasma for treating COVID-19. “I have seen one of my own patients with blood cancer quickly improve after receiving convalescent plasma. Similar stories that were often very detailed suggested that a formal study would help physicians with decisions they were already making on a daily basis.”

During the past year, over phone calls, emails and Zoom chats, updates on convalescent plasma — its historical success and its prospects for COVID-19 — were a staple in conversations between Henderson and his longtime friend and co-author Michael Thompson, MD, PhD, who also was his roommate during undergraduate school at the University of Wisconsin in Madison. Thompson is now an oncologist and hematologist at Advocate Aurora Health, and Advocate Aurora Research Institute, both in Wisconsin, as well as a member of the steering committee of the COVID-19 & Cancer Consortium.

“It became increasingly evident that patients with leukemia, lymphoma and other blood cancers were particularly susceptible to severe COVID-19 and that COVID-19 may develop in a unique way in these patients,” said Henderson. “We discussed that we might learn something from patients in the COVID-19 & Cancer Consortium, and things started to snowball from there.”

Henderson contacted fellow researchers in the COVID-19 Convalescent Plasma Program, including Michael J. Joyner, MD, who is a professor of anesthesiology at the Mayo Clinic and works closely with the FDA. Thompson reached out to Jeremy Warner, MD — a professor of medicine at Vanderbilt, a steering committee member of the COVID-19 consortium and who operates the CCC19 registry. Together, the researchers plumbed the group’s registry of de-identified data abstracted from medical records.

“The data started coming fast and furious,” Henderson recalled.

“Given that patients with blood cancers have higher mortality rates from COVID-19, we suspect our findings, along with other similar cases not in this database, support using convalescent plasma to improve survival in these patients,” Thompson said.

Henderson and Thompson contributed equally as the study’s first authors. Joyner is a co-author, and Warner is the senior author. “Despite the inevitable limitations of retrospective data, we find these results compelling and certainly hope that they will be quickly investigated in a prospective clinical trial,” Warner added. “We are exploring future research, including whether there is an interplay between patient factors and treatments received prior to the development of COVID-19, such as B-cell depleting monoclonal antibodies.”

This research is supported by the U.S. Department of Health and Human Services; Office of the Assistant Secretary for Preparedness and Response; Biomedical Advanced Research and Development Authority, contract no. 75A50120C00096; National Cancer Institute of the National Institutes for Health (NIH), grants P30 CA008748, P30 CA046592, P30 CA054174, P30 CA068485, T32 CA236621, and U01 CA231840; National Center for Advancing Translational Sciences of the NIH, grant UL1 TR002377; Schwab Charitable Fund (Eric E Schmidt, Wendy Schmidt donors); United Health Group; National Basketball Association; Millennium Pharmaceuticals; Octapharma USA Inc.; the American Cancer Society and Hope Foundation for Cancer Research, grant MRSG-16-152-01-CCE; the Longer Life Foundation: A RGA/Washington University Partnership; and the Mayo Clinic. The REDCap database is developed and supported by NCATS grant UL1 TR000445 awarded to the Vanderbilt Institute for Clinical and Translational Research.

Jeffrey Henderson disclosed the following potential conflict of interest: A grant from the Longer Life Foundation, an RGA/Washington University Partnership; and an unrestricted financial gift from Octapharma USA to Washington University to support COVID research in Henderson’s laboratory for this study. For other conflict of interest disclosures regarding the other authors, please go to JAMA Oncology for the study.

Featured image: Jeffrey P. Henderson, MD, PhD, an associate professor of medicine and of molecular microbiology at Washington University School of Medicine in St. Louis, holds a bag of convalescent plasma. He is an author on a new study that shows that such plasma from recovered COVID-19 patients can dramatically increase the likelihood of survival for blood cancer patients hospitalized with COVID-19. © Matt Miller


Reference: Thompson MA, Henderson JP, Shah PK, Rubinstein SM, Joyner MJ, Choueiri TK, Flora DB, Griffiths EA, Gulati AP, Hwang C, Koshkin VS, Papadopoulos EB, Robilotti EV, Su CT, Wulff-Burchfield EM, Xie Z, Yu PP, Mishra S, Senefeld JW, Shah DP, Warner JL. Convalescent Plasma and Survival in Hematologic Malignancy and COVID-19. JAMA Oncology. Published June 17, 2021. DOI: 10.1001/jamaoncol.2021.1799


Provided by Washington University School of Medicine at St. Louis

Low on Antibodies, Blood Cancer Patients Can Fight off COVID-19 with T Cells (Medicine)

New Penn Medicine Study Shows How T Cells Compensate When Other Immune Cells Go Down

Antibodies aren’t the only immune cells needed to fight off COVID-19 — T cells are equally important and can step up to do the job when antibodies are depleted, suggests a new Penn Medicine study of blood cancer patients with COVID-19 published in Nature Medicine. The researchers found that blood cancer patients with COVID-19 who had higher CD8 T cells, many of whom had depleted antibodies from cancer treatments, were more than three times likelier to survive than patients with lower levels of CD8 T cells.

“It’s clear T cells are critical in terms of the early infection and to help control the virus, but we also showed that they can compensate for B cell and antibody responses, which blood cancer patients are likely missing because of the drugs,” said co-senior author Alexander C. Huang, MD, an assistant professor of Hematology-Oncology in the Perelman School of Medicine at the University of Pennsylvania and Penn’s Institute of Immunology. “This is important when we think about how to improve the care of cancer patients with COVID. We need to maximize all the arms of the immune system, especially if we know that one particular arm of the immune system is down.”

Additionally, because the current COVID-19 mRNA vaccinations induce both antibody and T cell responses, the findings suggest that vaccination of blood cancer patients could provide protection through T cell immunity, despite the absence of antibodies.

The team—which included researchers from Memorial Sloan Kettering Cancer Center—studied hospitalized patients with both solid tumors and hematologic cancers admitted to four Penn Medicine hospitals and Memorial Sloan Kettering to better understand the immune determinants of COVID-19 deaths.

Supporting previous studies, patients with blood cancer were more likely to die from COVID-19 than patients with solid tumors or without cancer. Out of 100 patients admitted to Penn Medicine hospitals, 22 had a blood cancer diagnosis and were 2.6 fold more likely to die compared to patients with solid cancer, the authors found.

Immune profiling of 214 patient blood samples at Memorial Sloan Kettering and Penn Medicine revealed that patients with blood cancers, in particular patients treated with anti-CD20 antibodies, had decreased B cells and antibodies compared to patients with solid cancers and patients without cancer. Additional analyses also revealed that among patients with blood cancers, including patients treated with chemotherapy and anti-CD20 antibodies, those with higher CD8 T cell counts had a 3.6 fold greater likelihood of survival compared to those with lower counts.

Thus, the authors concluded, CD8 T cells may influence recovery from COVID-19 when B cells and antibodies are deficient.

“As a clinician, this work can help us advise patients while we wait for more vaccine specific studies to be published,” said first author Erin Bange, MD, a fellow in the division of Hematology-Oncology and Penn Center for Cancer Care Innovation. “We can inform patients that while their vaccine response likely will not be as robust as their friends/family who don’t have blood cancers, it is still critical and potentially lifesaving.”

The next step is to better understand the immune responses blood cancer patients with COVID-19 experience after they recover and how protective their immunity is without B cells and antibodies, the researchers said.

Co-authors on the study include Nicholas Han, a research assistant in Penn’s Institute of Immunology, Ronac Mamtani, MD, an assistant professor of Hematology-Oncology in Penn’s Perelman School of Medicine, and Santosha A.Vardhana, MD, PhD, a medical oncologist at Memorial Sloan Kettering.

The study was supported by the National Institutes of Health (CA230157, T32 T32CA009140, K08 AI136660, T32 T32-CA-09679, HL137006, T32 CA009140, AI155577, AI112521, AI082630, AI201085, AI123539, AI11795, T32CA009512), the Tara Miller Foundation, a Leukemia and Lymphoma Society Scholar in Clinical Research Award, the Allen Institute for Immunology, a ASCO Young Investigator Award, the Pershing Square Sohn Cancer Research Foundation, the Conrad Hilton Foundation, and the Parker Institute for Cancer Immunotherapy.


Provided by Penn Medicine

New Genetic Target for Blood Cancer Treatment (Biology)

Researchers have identified a vulnerability in some cases of acute myeloid leukaemia that could be harnessed for targeted treatment of these poor-prognosis cancers. 

Targeting a pathway that is essential for the survival of certain types of acute myeloid leukaemia could provide a new therapy avenue for patients, the latest research has found.

Researchers from the Wellcome Sanger Institute found that a specific genetic mutation, which is linked with poor prognosis in blood cancer, is involved in the development of the disease when combined with other mutations in mice and human cell lines.

The study, published today (30th April) in Nature Communications, provides a greater understanding of how the loss-of-function mutation in the CUX1 gene leads to the development and survival of acute myeloid leukaemia. The findings suggest that targeting a pathway that is essential for these cancer cells to continue growing could lead to new targeted therapies for some patients.

Acute myeloid leukaemia (AML) is an aggressive blood cancer that affects people of all ages, often requiring months of intensive chemotherapy and prolonged hospital admissions. It typically develops in cells within the bone marrow to crowd out the healthy cells, in turn leading to life-threatening infections and bleeding. Mainstream AML treatments have remained unchanged for decades and fewer than one in three people survive the cancer*.

Previously through large-scale DNA sequencing analysis, researchers at the Wellcome Sanger Institute found that loss-of-function mutations in the CUX1 gene on chromosome 7q were seen in several types of cancer, including AML, where it is associated with poor prognosis**. However, the role of this gene in AML development is unclear.

In this new study, the team used CRISPR/Cas9 gene-editing technology to show that lack of functioning CUX1 leads to expansion of certain types of blood stem cells, which are defective in a type of regulated cell death known as apoptosis. They found that the loss of CUX1 causes increased expression of the CFLAR gene — which encodes a protein that restrains apoptosis — potentially providing a means for mutated cancer cells to evade cell death and propagate. The researchers showed that targeting CFLAR, or apoptosis evasion pathways in general, could be a possible treatment for those living with this type of AML that is linked to poor prognosis. Currently, there are no clinically approved drugs that target CFLAR.

“By investigating the role of CUX1 further, we now have new insight into how this gene, and the lack of it when mutated, plays a key role in the survival of blood cancer cells. While this mutation doesn’t seem to cause the development of malignant disease on its own, focusing on the pathways involved with CUX1 is a good target for further research.”

Dr Saskia Rudat,co-first author and Postdoctoral Fellow at the Wellcome Sanger Institute

“By building on our previous analysis, this research has allowed us to gain crucial information about the development of this disease, and would not have been possible without the new and exciting CRISPR/Cas9 and genome sequencing technologies that enable us to investigate genetic weaknesses in cancer. Understanding more about the genetic basis of disease, and how multiple mutations come together to cause blood cancer is vital if we hope to save lives in the future.”

Dr Emmanuelle Supper,co-first author and Postdoctoral Fellow at the Wellcome Sanger Institute

“Acute myeloid leukaemia is a devastating disease, which is currently difficult to treat, especially in cases characterised by genetic lesions such as loss of CUX1 and chromosome 7q deletions. This new study provides evidence that could be used to help develop new targeted treatment for some people living with acute myeloid leukaemia, offering hope for this group of patients who unfortunately are more likely to have a poor prognosis.”

Dr Chi Wong,senior author and Wellcome Clinical Fellow at the Wellcome Sanger Institute and Honorary Consultant Haematologist at Addenbrooke’s Hospital

More information

* F. Ferrara, C.A. Schiffer.(2013) Acute myeloid leukaemia in adults. Lancet, 381, pp. 484-495

** Wong, C. C. et al.(2014) Inactivating CUX1 mutations promote tumorigenesis. Nat Genet 46, 33-38, doi:10.1038/ng.2846.

Publication:

Emmanuelle Supper, Saskia Rudat, Chi Wong, et al. (2021). Cut-like homeobox 1 (CUX1) tumor suppressor gene haploinsufficiency induces apoptosis evasion to sustain myeloid leukemia. Nature Communications. DOI: 10.1038/s41467-021-22750-8

Funding:

This research was funded by Wellcome, the Kay Kendall Leukaemia Fund, Cancer Research UK and an ERC Combat Cancer Programme award.

Featured image credit: Adobestock


Provided by Wellcome Sanger Institute

Scientists Discover “Jumping” Genes That Can Protect Against Blood Cancers (Medicine)

New research has uncovered a surprising role for so-called “jumping” genes that are a source of genetic mutations responsible for a number of human diseases. In the new study from Children’s Medical Center Research Institute at UT Southwestern (CRI), scientists made the unexpected discovery that these DNA sequences, also known as transposons, can protect against certain blood cancers.

These findings, published in Nature Genetics, led scientists to identify a new biomarker that could help predict how patients will respond to cancer therapies and find new therapeutic targets for acute myeloid leukemia (AML), the deadliest type of blood cancer in adults and children.

Transposons are DNA sequences that can move, or jump, from one location in the genome to another when activated. Though many different classes of transposons exist, scientists in the Xu laboratory focused on a type known as long interspersed element-1 (L1) retrotransposons. L1 sequences work by copying and then pasting themselves into different locations in the genome, which often leads to mutations that can cause diseases such as cancer. Nearly half of all cancers contain mutations caused by L1 insertion into other genes, particularly lung, colorectal, and head-and-neck cancers. The incidence of L1 mutations in blood cancers such as AML is extremely low, but the reasons why are poorly understood.

When researchers screened human AML cells to identify genes essential for cancer cell survival, they found MPP8, a known regulator of L1, to be selectively required by AML cells. Curious to understand the underlying basis of this connection, scientists in the Xu lab studied how L1 sequences were regulated in human and mouse leukemia cells. They made two key discoveries. The first was that MPP8 blocked the copying of L1 sequences in the cells that initiate AML. The second was that when the activity of L1 was turned on, it could impair the growth or survival of AML cells.

“Our initial finding was a surprise because it’s been long thought that activated transposons promote cancer development by generating genetic mutations. We found it was the opposite for blood cancers, and that decreased L1 activity was associated with worse clinical outcomes and therapy resistance in patients,” says Jian Xu, Ph.D., associate professor in CRI and senior author of the study.

MPP8 thus suppressed L1 in order to safeguard the cancer cell genome and allow AML-initiating cells to survive and proliferate. Cancer cells, just like healthy cells, need to maintain a stable genome to replicate. Too many mutations, like those created by L1 activity, can impair the replication of cancer cells. Researchers found L1 activation led to genome instability, which in turn activated a DNA damage response that triggered cell death or eliminated the cell’s ability to replicate itself. Xu believes this discovery may provide a mechanistic explanation for the unusual sensitivity of myeloid leukemia cells to DNA damage-inducing therapies that are currently used to treat patients.

“Our discovery that L1 activation can suppress the survival of certain blood cancers opens up the possibility of using it as a prognostic biomarker, and possibly leveraging its activity to target cancer cells without affecting normal cells,” says Xu.

Xu is an associate professor of pediatrics at UT Southwestern and a Cancer Prevention and Research Institute of Texas (CPRIT) Scholar in Cancer Research. Lead authors from the Xu lab include Zhimin Gu and Yuxuan Liu. Other collaborators include John Abrams and Alec Zhang from UT Southwestern, and Wenfeng An from South Dakota State University.

This work was supported by the National Institutes of Health (R01CA230631 and R01DK111430), CPRIT (RR140025, RP180504, RP180826 and RP190417), a Leukemia & Lymphoma Society Scholar award, an American Society of Hematology Scholar award, a Leukemia Texas Foundation research award, a Welch Foundation grant (I-1942), and donors to the Children’s Medical Center Foundation.

Featured image: Zhimin Gu, Ph.D., (left), postdoctoral fellow, Children’s Medical Center Research Institute at UT Southwestern (CRI), and a member of the Moody Medical Research Institute; Jian Xu Ph.D., associate professor, CRI. © UT Southwestern


Reference: Gu, Z., Liu, Y., Zhang, Y. et al. Silencing of LINE-1 retrotransposons is a selective dependency of myeloid leukemia. Nat Genet (2021). https://www.nature.com/articles/s41588-021-00829-8 https://doi.org/10.1038/s41588-021-00829-8


Provided by UT Southwestern Medical Center


About CRI

Children’s Medical Center Research Institute at UT Southwestern (CRI) is a joint venture of UT Southwestern Medical Center and Children’s Medical Center Dallas, the flagship hospital of Children’s Health. CRI’s mission is to perform transformative biomedical research to better understand the biological basis of disease. Located in Dallas, Texas, CRI is home to interdisciplinary groups of scientists and physicians pursuing research at the interface of regenerative medicine, cancer biology and metabolism. For more information, visit: cri.utsw.edu. To support CRI, visit: give.childrens.com/about-us/why-help/cri/.

About UT Southwestern Medical Center

UT Southwestern, one of the premier academic medical centers in the nation, integrates pioneering biomedical research with exceptional clinical care and education. The institution’s faculty has received six Nobel Prizes, and includes 23 members of the National Academy of Sciences, 17 members of the National Academy of Medicine, and 13 Howard Hughes Medical Institute Investigators. The full-time faculty of more than 2,800 is responsible for groundbreaking medical advances and is committed to translating science-driven research quickly to new clinical treatments. UT Southwestern physicians provide care in about 80 specialties to more than 105,000 hospitalized patients, nearly 370,000 emergency room cases, and oversee approximately 3 million outpatient visits a year.

A Potent Weapon Against Lymphomas (Medicine)

MDC researchers have developed a new approach to CAR T-cell therapy. The team has shown in Nature Communications that the procedure is very effective, especially when it comes to fighting follicular lymphomas and chronic lymphocytic leukemia, the most common type of blood cancer in adults.

The body’s defense system generally does not recognize cancer cells as dangerous. To correct this sometimes fatal error, researchers are investigating a clever new idea, one that involves taking a handful of immune cells from cancer patients and “upgrading” them in the laboratory so that they recognize certain surface proteins in the malignant cells. The researchers then multiply the immune cells and inject them back into the patients’ blood – setting them off on a journey through the body to detect and attack all cancer cells in a targeted way.

In fact, the first treatments based on this idea have already been approved: So-called CAR T cells have been used in Europe since 2018, particularly in patients with B-cell lymphomas for whom conventional cancer therapies have not worked.

T cells are like the immune system’s police force. The abbreviation CAR stands for “chimeric antigen receptor“ – meaning that the cellular police force is equipped with a new, laboratory-designed special antenna that targets a surface protein on the cancer cells. Thanks to this antenna, a small number of T cells can round up a large number of cancer cells and destroy them. Ideally, the CAR T cells patrol the body for weeks, months or even years and thus prevent tumor relapse.

A kind of signpost for B cells

Until now, the antenna on the CAR T cells was primarily directed against the protein CD19, which B cells – a type of immune cells – carry on their surface. Yet this form of therapy is by no means effective in all patients. A team led by Dr. Uta Höpken, head of the Microenvironmental Regulation in Autoimmunity and Cancer Lab at the Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), has now developed a new twist on this therapy that sensitizes the T cells in the laboratory to a different identifying feature: the B-cell homing protein CXCR5.

“CXCR5 was first described at the MDC more than 20 years ago, and I have been studying this protein myself for almost as long,” says Höpken. “I am therefore very pleased that we have now succeeded in using CXCR5 to effectively combat non-Hodgkin’s lymphomas, such as follicular and mantle cell lymphoma as well as chronic lymphocytic leukemias, in the laboratory.” This protein is a receptor that helps mature B cells move from the bone marrow – where they are produced – to immune system organs such as the lymph nodes and spleen. “Without the receptor, the B cells would not find their way to their target site, the B-cell follicles of these lymphoid organs,” Höpken explains.

Anti-CXCR5 CAR-T cells (green) attack lymphoma cells (magenta) within the stroma cell network of the B cell follicle (light blue). © AG Höpken / Rehm, MDC

A well-suited target

“All mature B cells, including malignant ones, carry this receptor on their surface. So it seemed to us to be well suited to detect B-cell tumors – thereby enabling CAR-T cells directed against CXCR5 to attack the cancer,” says Janina Pfeilschifter, a PhD student in Höpken’s team. She and Dr. Mario Bunse from the same research group are the lead authors of the paper, which appeared in the journal Nature Communications. “In our study, we have shown through experiments with human cancer cells and two mouse models that this immunotherapy is most likely safe and very effective,” says Pfeilschifter.

The new approach may be particularly well suited for patients with a follicular lymphoma or chronic lymphocytic leukemia (CLL). “Both types of cancer involve not only B cells but also follicular T helper cells, which also carry CXCR5 on their surface,” Bunse explains. The special antenna for the identifying feature, the CXCR5-CAR, was generated by Dr. Julia Bluhm during her time as a PhD student in the MDC’s Translational Tumorimmunology Lab, which is headed by physician Dr. Armin Rehm. He and Höpken are the corresponding authors of the study.

First successes in the petri dish

Pfeilschifter and Bunse first showed that various human cells, for example, from blood vessels, the gut and the brain, do not carry the CXCR5 receptor on their surface and are therefore not attacked in the petri dish by T cells equipped with CXCR5-CAR. “This is important to prevent unexpected organ damage from occurring during therapy,” Pfeilschifter explains. In contrast, experiments with human tumor cell lines showed that malignant B cells from very different forms of B-non-Hodgkin’s lymphoma all display the receptor.

Professor Jörg Westermann, from the Division of Hematology, Oncology and Tumor Immunology in the Medical Department of Charité – Universitätsmedizin Berlin at the Campus Virchow Clinic, also provided the team with tumor cells from patients with CLL or B-non-Hodgkin’s lymphomas. “There, too, we were able to detect CXCR5 on all B-lymphoma cells and follicular T helper cells,” Pfeilschifter says. When she and Bunse placed the tumor cells in the petri dish together with the CXCR5-targeted CAR T cells, almost all of the malignant B and T helper cells disappeared from the tissue sample after 48 hours.

Mice with leukemia were cured

The researchers also tested the new procedure on two mouse models. “The CAR T cells are infused into the blood of cancer patients,” Höpken says. “So animal research is needed to show that the cells home to the niches where the cancer resides, multiply there and then do their job effectively.”

“No laboratory can tackle such a study on its own. It has only come about thanks to a successful collaboration between many colleagues at the MDC and Charité.”, said Uta Höpken, Head of the lab “Microenvironmental Regulation in Autoimmunity and Cancer”.

One model consisted of animals with a severely suppressed immune system, which could therefore be treated with human CAR T cells without causing rejection reactions. “We also developed a pure mouse model for CLL specifically for the current study,” Bunse reports. “We administered mouse CAR T cells against CXCR5 to these animals by infusion and were able to eliminate mature B cells and T helper cells, including malignant ones, from the B-cell follicles of the lymphoid organs.”

The researchers discovered no serious side effects in the mice. “We know from experience with cancer patients that CAR T-cell therapy increases the risk of infection for a few months,” Rehm says. But in practice this side effect is almost always easily managed.

A clinical trial is in the works

”No laboratory can tackle such a study on its own,” Höpken emphasizes. “It has only come about thanks to a successful collaboration between many colleagues at the MDC and Charité.” For her, the study is the first step toward creating a “living drug” – similar to other cellular immunotherapies being developed at MDC. “We are already cooperating with two cancer specialists at Charité and are currently working with them to prepare a phase 1/2 clinical trial,” adds Höpken’s colleague Rehm. Both hope that the first patients will begin to benefit from their new CAR-T cell therapy in the near future.

The German José Carreras Leukemia Foundation has funded the research with around 240,000 euros over a period of three years. The non-profit organization supports forward-looking research projects and infrastructure projects that investigate the causes of leukemia and improve treatment, as well as social projects.

Reference: Bunse, M., Pfeilschifter, J., Bluhm, J. et al. CXCR5 CAR-T cells simultaneously target B cell non-Hodgkin’s lymphoma and tumor-supportive follicular T helper cells. Nat Commun 12, 240 (2021). https://www.nature.com/articles/s41467-020-20488-3 https://doi.org/10.1038/s41467-020-20488-3

Provided by Max Delbruck Center for Molecular Medicine

Cancer Researchers Identify Potential New Class of Drugs to Treat Blood and Bone Marrow Cancers (Medicine)

A new study by researchers in Cleveland Clinic’s Taussig Cancer Institute and Lerner Research Institute describes a novel class of targeted cancer drugs that may prove effective in treating certain common types of leukemia. The results first appeared online in Blood Cancer Discovery.

Myeloid leukemias are cancers derived from stem and progenitor cells in the bone marrow that give rise to all normal blood cells. One of the most common mutations involved in driving myeloid leukemias are found in the TET2 gene, which has been investigated for the last decade by Jaroslaw Maciejewski, MD, Ph.D., a practicing hematologist and chair of the Cleveland Clinic Department of Translational Hematology & Oncology Research.In the new study, Dr. Maciejewski and his collaborator in the Department of Translational Hematology & Oncology Research, Babal Kant Jha, Ph.D., report a new pharmacological strategy to preferentially target and eliminate leukemia cells with TET2 mutations.

“In preclinical models, we found that a synthetic molecule called TETi76 was able to target and kill the mutant cancer cells both in the early phases of disease—what we call clonal hematopoiesis of indeterminate potential, or CHIP—and in fully developed TET2 mutant myeloid leukemia,” said Dr. Maciejewski.

The research team designed TETi76 to replicate and amplify the effects of a natural molecule called 2HG (2-hydroxyglutarate), which inhibits the enzymatic activity of TET genes.The TET DNA dioxygenase gene family codes for enzymes that remove chemical groups from DNA molecules, which ultimately changes what genes are expressed and can contribute to the development and spread of disease.

While all members of the TET family are dioxygenases, the most powerful enzymatic activity belongs to TET2. Even when TET2 is mutated, however, its related genes TET1 and TET3 provide residual enzymatic activity. While significantly less, this activity is still enough to facilitate the spread of mutated cancer cells. Drs. Maciejewski’s and Jha’s new pharmacologic strategy to selectively eliminate TET2 mutant leukemia cells centers on targeting their reliance on this residual DNA dioxygenase activity.”We took lessons from the natural biological capabilities of 2HG,” explained Dr. Jha, a principal investigator.. “We studied the molecule and rationally designed a novel small molecule, synthesized by our chemistry group headed by James Phillips, Ph.D. Together, we generated TETi76—a similar, but more potent version capable of inhibiting not just TET2, but also the remaining disease-driving enzymatic activity of TET1 and TET3.”

The researchers studied TETi76’s effects in both preclinical disease and xenograft models (where human cancer cells are implanted into preclinical models). Additional studies will be critical to investigate the small molecule’s cancer-fighting capabilities in patients.”We are optimistic about our results, which show not just that TETi76 preferentially restricts the growth and spread of cells with TET2 mutations, but also gives survival advantage to normal stem and progenitor cells,” said Dr. Jha.

Myeloid leukiemias are commonly treated with chemotherapy, either alone or in combination with targeted drugs. More research is needed, but this early preclinical data suggest TETi76 may be a promising, more effective candidate to replace the targeted drugs currently used.

References: Yihong Guan et al, A Therapeutic Strategy for Preferential Targeting of TET2 Mutant and TET-dioxygenase Deficient Cells in Myeloid Neoplasms, Blood Cancer Discovery (2020). DOI: 10.1158/2643-3230.BCD-20-0173

Provided by Cleveland Clinic

Why Do Certain Chemotherapies Increase The Likelihood Of Blood Cancer?

In recent years, improvements in cancer therapy have led to a significant increase in cancer survivorship. Experts estimate that by 2022, the United States will have 18 million cancer survivors, but a subset of those survivors will have long-term health problems to be addressed.

One rare complication of cancer treatment is the development of a secondary blood cancer — therapy-related acute myeloid leukemia or myelodysplastic syndrome. These blood cancers are very aggressive and do not respond well to treatment. Historically, doctors thought that cancer treatments such as chemotherapy and radiation caused an accumulation of mutations in the blood that led to these therapy-related cancers.

In recent years, however, researchers have found that these mutations in the blood can also occur spontaneously with increasing age. This phenomenon is called clonal hematopoiesis (CH), and it’s found in 10 to 20% of all people over age 70. The presence of CH increases the risk of developing a blood cancer. Using data from MSK-IMPACTTM, Memorial Sloan Kettering’s clinical genomic sequencing test, researchers have shown that CH is also frequent in cancer patients.

In a study published in Nature Genetics on October 26, 2020, MSK investigators sought to understand the relationship between CH in cancer patients and the risk of later developing a treatment-related blood cancer. The study included data from 24,000 people treated at MSK. The researchers found CH in about one-third of them.

“Because many people treated at MSK have genetic testing done using MSK-IMPACT, we have this amazing resource that allows us to study CH in cancer patients at a scope that nobody else has been able to do,” says physician-scientist Kelly Bolton, lead author of the study.

Decoding Genetic Changes Specific to Cancer Treatment

Focusing on a subset of patients on whom they had more detailed data, the investigators observed increased rates of CH in people who had already received treatment. They made specific connections between cancer therapies such as radiation therapy and particular chemotherapies — for example certain platinum drugs or agents called topoisomerase II inhibitors — and the presence of CH.

Unlike the CH changes found in the general population, the team found that CH mutations after cancer treatment occur most frequently in the genes whose protein products protect the genome from damage. One of these genes is TP53, which is frequently referred to as “the guardian of the genome.”

The work was supported by the Precision Interception and Prevention (PIP) program at MSK, a multidisciplinary research program focused on identifying people who have the highest risk for developing cancer and improving methods for screening, early detection, and risk assessment.

The authors embarked on a three-year study to understand the relationship between CH and cancer therapy. For this part of the research, more than 500 people were screened for CH when they first came to MSK and then at a later point during their treatment. One finding from the study was that people with pre-existing CH whose blood carried mutations related to DNA damage repair such as TP53, were more likely to have those mutations grow after receiving cancer therapies, when compared to people who did not receive treatment.

“This finding provides a direct link between mutation type, specific therapies, and how these cells progress towards becoming a blood cancer,” says Elli Papaemmanuil of MSK’s Center for Computational Oncology, one of the two senior authors of the study. “Our hope is that this research will help us to understand the implications of having CH, and to begin to develop models that predict who with CH is at higher risk for developing a blood cancer.”

For a subset of patients with CH who developed therapy-related blood cancers, the researchers showed that blood cells acquired further mutations with time and progressed to leukemia. “We are now routinely screening our patients for the presence of CH mutations,” adds computational biologist Ahmet Zehir, Director of Clinical Bioinformatics and the study’s co-senior author. “The ability to introduce real-time CH screening for our patient population has allowed us to establish a clinic dedicated to caring for cancer patients with CH. As we continue to study more patients in the clinic, we expect to learn more about how to use these findings to find ways to detect treatment-related blood cancers early when they may be more treatable.”

Applying Findings to Future Treatments

In the future, this research may help to guide therapy by indicating whether some chemotherapy drugs are more appropriate than others in people with CH. People who are at a high risk of developing a treatment-related leukemia also may benefit from a different treatment schedule. “We hope that this research will allow us to ultimately map which CH mutations a person has and use that information to tailor their primary care and also mitigate the long-term risk of developing blood cancer,” Dr. Papaemmanuil says.

“We explored this in collaboration with investigators from the National Cancer Institute, Dana-Farber Cancer Institute, Moffit Cancer Center, and MD Anderson, and showed that such risk-adapted treatment decisions could achieve significant reduction of leukemia risk, without affecting outcomes for the primary cancer,” Dr. Bolton adds.

The investigators also hope to use the data from this study to develop better methods for detecting CH-related blood cancers when they first begin to form — and potentially to develop new interventions that could prevent CH from ever progressing to cancer. “We’re excited about the idea of continuing to grow and expand the CH clinic as part of the integrated vision of PIP,” says physician-scientist Ross Levine, who leads MSK’s CH clinic and is a member of the Human Oncology and Pathogenesis Program.

“In addition to continuing to follow people who are at the highest risk of developing a secondary cancer, we want to continue to use the clinic as a vehicle for studies like this,” he adds. “Our long-term goal is to move toward therapeutic interventions and preventing disease in a way that we’ve never been able to do before.”

References: Bolton, K.L., Ptashkin, R.N., Gao, T. et al. Cancer therapy shapes the fitness landscape of clonal hematopoiesis. Nat Genet (2020). https://doi.org/10.1038/s41588-020-00710-0 link: https://www.nature.com/articles/s41588-020-00710-0

Provided by MSKCC

New Blood Cancer Treatment Works By Selectively Interfering With Cancer Cell Signalling (Medicine)

UAlberta research sets the stage for imminent human trials of B-cell lymphoma treatment.

University of Alberta scientists have identified the mechanism of action behind a new type of precision cancer drug for blood cancers that is set for human trials, according to research published today in Nature Communications.

University of Alberta scientist Luc Berthiaume and his team have identified the mechanism of action behind a new type of precision cancer drug for blood cancers. The team plans to soon initiate Phase 1 trials of PCLX-001 in lymphoma, leukemia, breast and colon cancer patients. ©Ryan Parker.

The research team led by Luc Berthiaume, cell biology professor in the Faculty of Medicine & Dentistry, spent four years working to understand how the compound PCLX-001 targets enzymes that perform myristoylation, a cellular process in which the fatty acid myristate modifies proteins so they can move to membranes and become part of the cell signalling system.

“The enzymes that transfer myristate onto proteins are overexpressed in some cancer cells, meaning there’s more of those enzymes, so they have long been thought of as a logical target for cancer treatment,” said Berthiaume, who is also chief scientific officer and co-founder of Pacylex Pharmaceuticals, the U of A spinoff company developing the drug.

“Until now no one has done a thorough analysis of this hypothesis,” Berthiaume said. “We actually found that several types of cancer cells have fewer of these enzymes, making them seemingly easier to kill with our lead drug.”

To demonstrate this, the researchers tested the drug against 300 different cancer cell types. They reported that blood cancer cells including lymphomas and leukemia, which have fewer of the enzymes, are extremely sensitive to the drug. It also killed other types of cancer cells when given at a higher concentration.

The team found that the drug stopped B-cell lymphoma tumour survival signals, killed B-cell tumour cells in both test-tube and animal experiments, and left non-cancerous cells unharmed, Berthiaume said.

Having completed the necessary biosafety studies, Pacylex plans to initiate Phase 1 trials of PCLX-001 in lymphoma, leukemia, breast and colon cancer patients at the Cross Cancer Institute in Edmonton, the B.C. Cancer Centre in Vancouver and Princess Margaret Cancer Centre in Toronto later this year, Berthiaume said.

“We think PCLX-001 is a compound with a large therapeutic window that can kill the cancer cells at a much lower concentration than what is needed to kill normal cells,” he said. “That is the holy grail of cancer therapies.” “Because of the highly selective nature of our drug, it’s often referred to as a precision medicine, and we anticipate minimal side-effects,” he said.

References: Beauchamp, E., Yap, M.C., Iyer, A. et al. Targeting N-myristoylation for therapy of B-cell lymphomas. Nat Commun 11, 5348 (2020). https://doi.org/10.1038/s41467-020-18998-1 link: https://www.nature.com/articles/s41467-020-18998-1

Provided by University Of Alberta Faculty Of Medicine And Dentistry