Stem Cell Clinic

Cellular Therapies Fill Unmet Needs in R/R Multiple Myeloma – Targeted Oncology

Innovative approaches in multiple myeloma that focus on cellular therapies offer hope to patients with multiple myeloma.

Current approaches for multiple myeloma are stratified by patient fitness and age. For patients who can tolerate them, 3- or 4-drug combinations, with or without an autologous stem cell transplant (ASCT), can result in a complete remission, ideally with no residual disease. For patients who are elderly or fragile, 2-drug or 3-drug regimens are the standard.

For the standard-risk patient, a regimen of bortezomib (Velcade), lenalidomide (Revlimid), and dexamethasone (VRd) plus a CD38 monoclonal antibody such as daratumumab (Darzalex) or isatuximab (Sarclisa) is the norm. As a whole, these combinatorial approaches are needed because multiple myeloma is a heterogenous disease whose optimal treatment takes advantage of multiple mechanisms of action. These regimens can result in first remissions that range from 4 to 5 years.

Although these outcomes are promising, there is still an unmet need for patients with relapsed or refractory disease. Innovative approaches in multiple myeloma that focus on cellular therapies offer hope to these patients.

In a presentation during the 39th Annual CFS Innovative Cancer Therapy for Tomorrow, Shambavi Richard, MD, an assistant professor in medicine, hematology, and medical oncology at The Mount Sinai Hospital in New York, New York, addressed the emerging therapeutic frontiers in multiple myeloma with a focus on chimeric antigen receptor (CAR) approaches and bispecific antibodies.1 Richard explored updated results from the KarMMa trial (NCT03361748), which enrolled 149 patients with relapsed/refractory multiple myeloma (RRMM) and who were previously exposed to immunomodulatory agents, proteasome inhibitors (PIs), and CD38 antibodies (mAbs) and reported poor outcomes. Evaluable patients received idecabtagene vicleucel (ide-cel; n = 128).2,3

At a median follow-up of 15.4 months, the objective response rate (ORR) was 73% and median progression-free survival (PFS) was 8.8 months for all treated patients (TABLE3 ). Investigators reported that at the highest targeted dose of 450 106 CAR T cells, the overall response rate (ORR) was 81%, the complete response (CR) rate was 39%, and the median PFS increased by 12.2 months with longer follow-up. In a subgroup analysis of difficult-to-treat patients, the ORR for patients with extramedullary disease was 70%; patients with high-tumor burden, 71%; and patients with R-ISS stage III disease, 48%.

Regarding safety, 97% of patients had cytopenia and 89% had grade 3/4 neutropenia; 52% experienced thrombocytopenia and 60% developed anemia. Cytokine release syndrome (CRS) had a median onset of 1 day, with a median duration of 5 days. CRS was seen in 84% of patients but grade 3/4 was observed in only 6% of patients. Neurologic toxicity was observed in 18% of patients and 4% were grade 3/4.

Updated results from the CARTITUDE-1 trial (NCT03548207)4 showed that ciltacabtagene autoleucel (cilta-cel) yielded early, deep, and durable responses in heavily pretreated patients with multiple myeloma, with a manageable safety profile at the recommended phase 2 dose.

In the study, 97 patients with a median of 6 prior lines received cilta-cel. The overall response rate per independent review committee (primary end point) was 97% (95% CI, 91%-99%), with 67% of patients achieving stringent CR (sCR). The median time to first response was 1 month (range, 1-9), and median time to CR or better was 2 months (range, 1-15). Responses deepened over time, and the median duration of response was not reached. Of 57 patients evaluable for minimal residual disease (MRD) assessment, 93% were MRD-negative at 10-5. The 12-month PFS and overall survival (OS) rates (95% CI) were 77% (66%-84%) and 89% (80%-94%), respectively; the median PFS was not reached.

In terms of adverse events, neutropenia was 94.8% grade 3/4, and 60.8% of patients had grade 3/4 anemia, said Richard. CRS was almost universal, with any-grade CRS seen in 94.8% of patients. This was a little different compared with ido-cel in terms of time of onset, which was 7 days with this product vs 1 day with the ido-cell product, she said. In both of these trials, early death within the first 2 to 3 months was 2% or less.

When comparing ide-cel to conventional treatment, according to findings presented by Shah et al,5 the investigators observed that ide-cel was associated with a significantly higher ORR compared with conventional treatment (OR, 5.11; 95% CI, 2.92-8.94; P < .001). Similarly, ide-cel significantly extended PFS (HR, 0.55; 95% CI, 0.42-0.73; P < .001) and OS (HR, 0.36; 95% CI, 0.24-0.54; P < .001) vs conventional treatment. Richard said this analysis aimed to compare efficacy outcomes observed with ide-cel treatment in KarMMa and conventional treatment in the Monoclonal Antibodies in Multiple Myeloma: Outcomes After Therapy Failure (MAMMOTH) study.6 Investigators analyzed outcomes of 275 patients with multiple myeloma with disease refractory to CD38 monoclonal antibodies at 14 academic centers.

Turning to the challenge of resistance to therapies in multiple myeloma, Richard noted that there are 3 main strategies in play: multiple myelomacell directed, T-cell directed; and CAR construct.

Possible strategies employed that use multiple myeloma celldirected treatments involve pooling CAR T products with different antigens; using dual CAR products that are constructed using 2 antigen specifi cities, such as B-cell maturation antigen (BCMA)/CD19; or taking a tandem CAR approach. Investigators also can focus on alternate antigens including SLAMF7, CD138, or integrin beta7.

Strategies that are T-cell directed can focus on those that are enriched for central or stem cell memory T cells or use combination approaches with checkpoint inhibitors or immunomodulatory imide drugs and cereblon E3 ligase modulators (CelMoD).

Efforts that tweak the CAR construct are also undergoing evaluation. These include FasTCAR, in which manufacturing takes 24 to 36 hours; next-generation CARs, which are armored CAR T cells that prevent T-cell exhaustion; CARs that use a safety switch to mitigate adverse effects; and allogeneic CARS.

Richard highlighted results from a study evaluating teclistamab, a bispecific antibody that binds to BCMA and CD3 to redirect T cells to attack multiple myeloma cells.

Findings from MajesTEC-1 (NCT03145181) demonstrated that the ORR in response-evaluable patients treated at the recommended phase 2 dose (n = 40) was 65% (95% CI, 48%-79%); 58% achieved a very good partial response or better.7 At the recommended phase 2 dose, the median duration of response was not reached. After 7.1 months median follow-up, 22 (85%) of 26 responders were alive and continuing treatment. During the 2021 American Society of Clinical Oncology Annual Meeting, Krishnan et al presented updated findings showing 58% of evaluable patients had achieved a very good partial response or better and 30% had achieved a CR or better; the median time to first confirmed response was 1.0 month (range, 0.2-3.1).8

Another bispecific antibody, talquetamab, has continued to show promising clinical activity in patients with RRMM. Updated findings from a phase 1 trial (NCT03399799)9 showed the ORR at the recommended phase 2 dose (RP2D) in response-evaluable patients (n = 24) was 63%, with 50% reaching very good partial response or better; 9/17 (53%) evaluable patients with triple-class refractory disease and 3/3 (100%) patients who were penta-refractory had a response. Median time to first confirmed response at the RP2D was 1.0 month (range, 0.2-3.8). Overall, responses were durable and deepened over time (median follow-up, 6.2 months [range, 2.7-9.7+] for responders at the RP2D).

When comparing CAR T-cell therapy to bispecific antibodies, Richard noted that patients undergo CAR T-cell therapy once with no further therapy indicated. Additionally, patients can enjoy a long chemotherapy holiday, whereas bispecific antibodies require more frequent doses. Toxicities are similar for the 2 approaches, although Richard said that CRS can be slightly more profound and at a somewhat higher grade with the CAR T-cell approach compared with that of bispecific antibodies.

In conclusion, Richard also noted that the costs associated with both these approaches will have an impact, especially in high up-front costs. Bispecific c antibodies, however, due to their chronic recurrent administration, may also come with a long-term financial burden.

REFERENCES:

1. Richard S. New therapeutic frontiers for RRMM: CAR T and bispecifi c antibodies. Presented at: 39th Annual CFS. Chemotherapy Foundation Symposium. Innovative Cancer Therapy for Tomorrow. November 3-5, 2021; New York, NY.

2. Munshi NC, Anderson LD Jr, Shah N, et al. Idecabtagene Vicleucel in Relapsed and Refractory Multiple Myeloma. N Engl J Med. 2021;384(8):705-716. doi:10.1056/NEJMoa2024850

3. Anderson LD, Munshi NC, Shah N, et al. Idecabtagene vicleucel (ide-cel, bb2121), a BCMA-directed CAR T cell therapy, in relapsed and refractory multiple myeloma: Updated KarMMa results. J Clin Oncol. 2021;39(suppl 15):8016-8016. doi: 10.1200/JCO.2021.39.15_suppl.8016

4. Usmani SZ, Berdeja JG, Madduri D, et al. Ciltacabtagene autoleucel, a B-cell maturation antigen-directed chimeric antigen receptor T-cell therapy, in relapsed/refractory multiple myeloma: updated results from CARTITUDE-1. J Clin Oncol. 2021;39(suppl 15; abstr 8005). doi: 10.1200/JCO.2021.39.15_suppl.8005

5. Shah N, Ayers D, Davies FE, et al. A matching-adjusted indirect comparison of efficacy outcomes for idecabtagene vicleucel (ide-cel, bb2121), a BCMA-directed CAR T cell therapy versus conventional care in triple-class-exposed relapsed and refractory multiple myeloma. Presented at: 62nd American Society of Hematology Meeting and Exposition, December 5-8, 2020. Abstract 1653. https://bit.ly/3nQb458

6. Gandhi UH, Cornell RF, Lakshman A, et al. Outcomes of patients with multiple myeloma refractory to CD38-targeted monoclonal antibody therapy. Leukemia. 2019;33(9):2266-2275. doi:10.1038/ s41375-019-0435-7

7. Usmani SZ, Garfall AL, van de Donk NWCJ, et al. Teclistamab, a B-cell maturation antigen CD3 bispecific antibody, in patients with relapsed or refractory multiple myeloma (MajesTEC-1): a multicentre, open-label, single-arm, phase 1 study. Lancet. 2021;398(10301):665- 674. doi:10.1016/S0140-6736(21)01338-6

8. Krishnan AY, Garfall Al, Mateos M-V, et al. J Clinical Oncol. 2021;39(suppl 15):8007-8007. doi: 10.1200/JCO.2021.39.15_suppl.8007

9. Berdeja JG, Krishnan AY, Oriol A, et al. Updated results of a phase 1, first-in-human study of talquetamab, a G protein-coupled receptor family C group 5 member D (GPRC5D) CD3 bispecific antibody, in relapsed/refractory multiple myeloma (MM). J Clin Oncol. 2021;39(suppl 15):8008. doi: 10.1200/JCO.2021.39.15_suppl.8008

Originally posted here:
Cellular Therapies Fill Unmet Needs in R/R Multiple Myeloma - Targeted Oncology

COVID-19 Takes a Toll on People with Blood Cancers and Disorders – Cancer Health Treatment News

As the COVID-19 pandemic continues to evolve, five studies presented during the 63rd American Society of Hematology (ASH) Annual Meeting and Exposition shed light on the persisting burden that COVID-19 has had on people with underlying blood disorders.

We take care of the patients at the highest risk for COVID-19 illness and those who are among the least likely to respond to the vaccine; these and other studies underscore the dual vulnerability facing many of our patients, said press briefing moderator,Laura Michaelis, MD, of the Medical College of Wisconsin. Hematologists have continued to play a unique role in contributing to the emerging science of COVID-19, especially given our expertise in clotting, and ASH has continued to provide leadership in an uncertain time with vetted resources and timely guidance for how best to manage our patients amid the pandemic.

Two studies analyze data from theASH Research Collaborative (ASH RC) COVID-19 Registry for Hematology, which started in the early days of the pandemic to provide real-time observational data summaries to clinicians on the front lines of the fight against COVID-19, as well as researchers and providers around the world.

In September 2021, the Centers for Disease Control and Prevention (CDC) awarded the ASH RC funding to identify the overall burden of COVID-19, the effects of health disparities and outcomes, and the areas where future resources should be focused for treatment for people living with hematologic malignancies. Specifically, CDC funding, in part, supports additional data submissions to the ASH RC COVID-19 Registry, real-time public data summaries, and research activities. As the Registry dataset has grown, researchers have identified potential drivers of severe illness, hospitalization, and mortality. The data also suggest that aggressive supportive treatment of COVID-19 can improve outcomes for many patients and should be offered.

A third study conducted among individuals living with sickle cell disease suggests COVID-19 infection can cause occlusive events, resulting in pain episodes, but these patients seem to respond to COVID-19 treatments and also were quick to adopt precautions and shift to virtual appointments as needed.

The final two studies look at antibody response following vaccination among people with various hematologic malignancies, helping give clues into which groups of patients may still be at high risk of COVID-19 after getting the vaccines.

A number of studies have shown that people with blood cancers have less than optimal responses to vaccination, and there is a need to continue to push for mitigation strategies, said Dr. Michaelis.

Abstract 3040: Risks for Hospitalization and Death Among Patients with Blood Disorders from the ASH RC COVID-19 Registry for Hematology

Patients with blood cancers, particularly those with more advanced disease, are especially vulnerable to serious COVID-19 outcomes, including an elevated chance of severe illness and death from COVID-19, according to an analysis of more than 1,000 patients in the ASH RC COVID-19 Registry for Hematology. Based on the report, 17% of patients with blood cancers who developed COVID-19 died from COVID-related illness, a strikingly higher mortality rate than what was seen in the general population, according to researchers. Older age, male sex, poor cancer prognosis, and electing to defer intensive care when it was recommended were all independently associated with a heightened chance of dying.

In our analysis, having a poor prognosis for underlying disease prior to COVID-19 and deciding to forgo ICU-level care for that disease were the most powerful predictors of mortality among patients with blood cancer and COVID-19and the two may very well be related, saidLisa K. Hicks, MD, MSc, of St. Michaels Hospital in Toronto, Canada. If someone is sick enough to require ICU-level care and their preference is not to receive this type of care, we would expect that decision to have a major impact on their survival.

According to the data, patients whose physician had estimated that they had less than six months to live due to their cancer before getting COVID-19 had six-fold higher odds of dying and these odds nearly doubled among people who decided to forgo more intensive care due to COVID-19. However, these groups represented a small proportion of the overall sample with only 7% estimated to have a pre-COVID-19 prognosis of under six months, and 9% deferring ICU care.

Of particular interest to the field was whether blood cancer treatment would affect COVID-19 mortality. Most patients included in the dataset (71%) received cancer treatment during the previous year; others were either in remission or had not yet needed treatment. In addition, receiving cancer treatment in the year prior to COVID-19 infection did not significantly increase the risk of death as some had feared; however, it was linked to an increased risk of hospitalization if infected by COVID-19. Older age, being male, having active cancer, and having other health conditions were also associated with an increased risk of hospitalization from COVID-19 among patients with blood cancers.

In the early days of the pandemic, there was a lot of uncertainty about whether we should withhold or modify blood cancer treatments in regions with high levels of COVID-19, said Dr. Hicks. The data are somewhat reassuring in that, while recent cancer treatment was linked to a higher risk of hospitalization among those with blood cancer and COVID-19, it wasnt independently associated with a statistically greater likelihood of dying. The type of blood cancer was also not associated with a higher risk of COVID-19 mortality. These findings suggest that patients who need treatment for their hematologic malignancy should likely proceed with that treatment.

Data were collected between April 1, 2020, and July 2, 2021, as part of the ASH RCs COVID-19 Registry for Hematology, which is a public-facing, volunteer registry reporting outcomes of COVID-19 infection in patients with underlying blood disorders. A total of 1,029 patients from around the globe were included in this analysis. Of these, 41% were female. The median age was 50 to 59 years of age, and patients ranged from five to more than 90 years of age; 27% had at least one co-existing condition such as heart disease, hypertension, respiratory disease, or diabetes. Researchers sought to identify factors associated with a higher likelihood of hospitalization and death from COVID-19.

Of people included in the analysis, 354 (34%) had acute leukemia or myelodysplastic syndromes (MDS), 255 (25%) had lymphoma, 206 (20%) had plasma cell dyscrasia (myeloma/amyloid/POEMS), 116 (11%) had chronic lymphocytic leukemia (CLL), and 98 (10%) had myeloproliferative neoplasm (MPN).

Patients with MPN and plasma cell dyscrasia had less severe COVID-19 illness overall compared to patients with CLL, leukemia, MDS, or lymphoma, which Dr. Hicks said is not surprising as patients with MPN typically live with their disease for many years, are generally in better health, and may not require immunosuppressive treatment.

The data from the ASH RC COVID-19 Registry has limitations and findings should generally be regarded as hypothesis generating, Dr. Hicks said. Nonetheless, the data do suggest that patients with blood cancers are at substantial risk from COVID-19; this finding has implications for our patients, how we manage our clinics amid COVID-19 and the changing variants, and how vaccines, boosters, and antibody treatments are distributed.

In this analysis, 17% of those with blood cancers died of COVID-19; the mortality rate among those infected with SARS-CoV-2 in the general U.S. population has been reported to be between 1.6% and 6.2% at various times during the pandemic, Dr. Hicks added.

The ASH RC Registry is a public voluntary registry that continues to accrue cases and provide the information on a public dashboard to help keep the hematology community apprised on changing trends. Dr. Hicks said the team will also be looking at how the risks of hospitalization and death changed as vaccines and COVID-19 treatments became more widely available.

Abstract 2800: Clinical Predictors of Outcome in Adult Patients with Acute Leukemias and Myelodysplastic Syndrome and COVID-19 Infection: Report from the American Society of Hematology Research Collaborative (ASH RC) Data Hub

In separate analyses of 257 patients with acute leukemia or MDS who developed COVID-19 and are part of the ASH RC COVID-19 Registry for Hematology, both neutropenia (a type of low white blood cell count) and having active MDS or leukemia (versus being in remission) were found to strongly and independently predict severe COVID-19 illness.Once hospitalized, active disease by itself whether someone was newly diagnosed or had relapsed was not tied to a greater odds of dying from COVID-19, nor was receiving ongoing cancer treatment.

For this retrospective analysis, which included data from 135 patients with acute myeloid leukemia (AML), 82 with acute lymphocytic leukemia (ALL) and 40 with MDS who were diagnosed with COVID-19 from 2019 to present, researchers sought to identify characteristics that put patients at higher risk of severe illness or death from COVID-19. At the time of COVID-19 diagnosis, 46% were in remission and 44% had active disease.

COVID-19 severity was defined as mild (no hospitalization required), moderate (hospitalization required), or severe (ICU admission required). After adjusting for several risk factors, active disease and neutropenia at the time of COVID-19 diagnosis were also associated with severe COVID-19 illness that necessitated ICU-level care.

Overall, one out of five (21%) patients died from COVID-19, which was higher than the mortality rate reported for the registry as a whole (17%) or what was seen in the general public during the same period of time, researchers reported. Mortality among hospitalized patients with COVID-related illness was 34%, and mortality among patients once admitted in the ICU was 68%. The two factors most strongly associated with a higher likelihood of dying among these patients were: 1) how long someone was perceived to live from the underlying MDS or leukemia before getting COVID-19, as defined as a physicians estimated prognosis of less than six months survival, and 2) whether or not they decided to go to the ICU if it was recommended. Older age, male sex, and neutropenia at diagnosis were also associated with COVID-19 mortality though less strongly.

This is a particularly vulnerable population and we suspected they may do worse because they are immunocompromised and, as it is, the average survival for acute blood cancers if untreated is three to six months, so if COVID-19 comes together with that diagnosis, its very concerning, saidPinkal Desai, MD, MPH, of Weill Cornell Medical College, New York. Our data suggest these patients can survive COVID-19 and their underlying disease itself was not associated with worse mortality, which means that if these patients are given appropriate and aggressive treatment, we can help them recover. But if there are decisions that are made after they get to the hospital (for example, whether to go to the ICU) that clearly plays a role.

In fact, patients for whom ICU-level care was recommended and declined had five times higher odds of dying compared with patients who opted to go to the ICU.

Patients who went to the ICU did better regardless of disease status, said Dr. Desai. Just having acute leukemia or MDS puts these patients at high risk of severe COVID-19, and they need to be hospitalized and receive treatments, but decisions about the ICU should be individualized, a patients prognosis should be discussed, and if a patient wants aggressive care for COVID-19 that should be offered.

Patients were more likely to forgo ICU care if they were older, male, smokers, or if they had active disease or an estimated pre-COVID-19 survival of less than six months. Forgoing ICU care was associated with a higher COVID-19 mortality in all patients.

Our data show that these patients do survive COVID-19 after receiving care in the ICU and underscore that cancer treatments should not be withheld as inferior treatment would quickly put many of these patients into the category of a prognosis of less than six months, said Dr. Desai. COVID-19 vaccination is also critically important.

The data are limited in that they were collected before COVID-19 vaccines were widely available; future data should inform about mortality rates among vaccinated patients.

Patient Vigilance and Virtual Visits Credited for Reducing Exposure, Illness, and Death Due to COVID-19 in Cohort With Sickle Cell Disease

Abstract 3105: COVID-19 Infection and Outcomes at a Comprehensive Sickle Cell Center

The Georgia Comprehensive Sickle Cell Center at Grady Hospital in Atlanta the nations largest treatment center for adults living with sickle cell disease (SCD) quickly switched to offering virtual visits for routine follow-up care of its more than 1,300 patients as the COVID-19 pandemic emerged. People living with SCD, an inherited disorder characterized by crescent- or sickle-shaped red blood cells, are immunocompromised and thus at high risk for COVID-19. The center established a database to track all COVID-19 cases among its patients.

The first report from that database the largest single-center study to date on COVID-19 in people with SCD now shows that between March 2020 and March 2021, just 55 (4%) of the centers 1,343 patients contracted COVID-19, of whom 16 (29%) were hospitalized and two ultimately died from complications of infection with the virus. Eleven patients (20%) required neither hospitalization nor emergency-room treatment for complications of either COVID-19 or SCD during the one-year follow-up period.

Our findings show that when supported by virtual visits, most of our patients successfully reduced their exposure to and complications from COVID-19, said study authorFuad El Rassi, MD, of Emory University and director of research at the Grady Comprehensive Sickle Cell Center. They understood the risks and followed recommendations to stay at home and avoid interacting with other people.

The 55 patients who contracted COVID-19 were aged 28 on average and 51% were female. Of those who visited an emergency room or were hospitalized during the year of follow-up, 27 (49%) sought care for a painful episode of SCD and 15 (27%) for complications of COVID-19. Among those who sought care for COVID-19 symptoms, 32 (58%) had pain as their primary symptom, followed by cough and fever (40%) and shortness of breath (31%); 25% had chest X-ray evidence of pneumonia. Sixteen patients received treatment, with nine receiving the antibody treatment remdesivir, eight receiving the steroid drug dexamethasone, and seven receiving red-blood-cell products to treat pain.

Twenty cases of COVID-19 were diagnosed between March and September of 2020. The two patient deaths from COVID-19 occurred in June and July of 2020. Among the 35 cases diagnosed between October 2020 and March 2021, no patients died and the number of hospitalizations decreased as better treatments for COVID-19 became available.

One of the patient deaths was due to a blood clot in the lungs, Dr. El Rassi said. This unfortunately occurred before it became the standard of care to treat hospitalized COVID-19 patients with blood thinners, he said.

Despite the second peak in COVID-19 cases in the winter of 2021, there were no reported deaths among our patients who developed the disease, Dr. El Rassi added. This suggests that the patients vigilance in staying home may have been crucial to reducing illness and death, and having the option for virtual visits was also key. Patients who needed blood tests or to obtain medication refills were sent to satellite centers.

Patient adherence to COVID-19 precautions was measured based on their responses to physician questions at intake and during virtual follow-up visits.

Dr. El Rassi and his colleagues plan to conduct further studies to evaluate the impact of the delta variant on diagnosis, illness, and death from COVID-19 among the sickle cell centers patients.

Some People With Blood Disorders May Continue to Face High Risk of COVID-19 After Vaccination

Abstract 218: Antibody Response to Vaccination with BNT162b2, mRNA-1273, and ChADOx1 in Patients with Myeloid and Lymphoid Neoplasms

According to a new study, about 15% of people with blood cancers and other blood disorders had no vaccination-related antibodies after receiving a COVID-19 vaccine. While researchers say it is encouraging that 85% of study participants did show an antibody response, the findings suggest that additional precautions may be warranted to prevent COVID-19 infection among people with blood disorders.

The study examined antibody levels after COVID-19 vaccination in people with blood cancers such as lymphoid and myeloid neoplasms, autoimmune disorders, and non-cancerous disorders of blood or immune cells. The results suggest that patients with lymphoma and those currently receiving treatment are the least likely to build antibodies in response to a COVID-19 vaccine.

Some patients with hematologic diseases do not have an adequate antibody response and might, therefore, not have sufficient protection from vaccination, saidSusanne Saussele, MD, of III. Medizinische Klinik, Medizinische Fakultt Mannheim, Universitt Heidelberg, Germany. This study can help guide vaccination strategies for these patients. In addition, our study suggests that when it is possible to delay beginning treatment for their underlying disorder, it may be best to wait so that a patient can receive a vaccine or booster first.

People with blood disorders face a high risk of hospitalization and death if they become infected with COVID-19, especially if they are older or have received therapies that reduce B-cells, a type of immune cell. Since the majority of participants in the study did respond to COVID-19 vaccines, the results underscore the role of vaccination as an important strategy for preventing severe disease, researchers said. However, the findings also suggest vaccination should be complemented with other precautions. We should recommend ongoing protective measures such as masks, social distancing, and screenings, as well as prioritizing vaccination for family members and caregivers to protect the patients, Dr. Saussele said.

For the study, the researchers recruited 373 patients treated for blood disorders at University hospital Mannheim in Germany and measured vaccine-related antibodies in their blood a median of 12 weeks after final vaccination. More than 90% of participants had blood cancer, while 9% had either autoimmune disease or a non-malignant blood disorder. Most patients had received the Pfizer-BioNTech [BNT162b2]vaccine; 10% received the Moderna vaccine [mRNA-1273], 7% received the AstraZeneca vaccine [ChADOx1], and 6% received one dose from each of the two vaccine types.

Overall, 85% of participants tested positive for vaccine-related antibodies and 15% tested negative. The rate of negative antibody results was highest among those with lymphoid neoplasms, a group of diseases that include lymphoma, myeloma, and lymphoid leukemia. Among these patients, 36% tested negative for vaccine-related antibodies. Patients with indolent non-Hodgkin lymphoma, a slow-growing type of lymphoma, had the weakest response to vaccination overall.

Being on active therapy was associated with a reduced antibody response. Overall, 61% of study participants were on active therapy. Of those who tested negative for vaccine-related antibodies, most (71%) were on active therapy. Therapies correlated with a negative response were rituximab, ibrutinib/acalabrutinib, and ruxolitinib.

Our study suggests that most people with blood malignancies not only those who are currently under treatment should monitor their antibody levels and work closely with their care team to determine how to continue to protect themselves from COVID-19, Dr. Saussele said. Antibody measurements offer a hint of who has responded to the vaccine and can perhaps ease up on precautions a bit.

Dr. Saussele noted that the results are limited in that the study did not examine participants T-cell response to vaccination, meaning that some patients level of protection may have been underestimated. The researchers plan to continue to measure antibody levels for at least a year and to assess participants rates of breakthrough infections and response to vaccine boosters.

Strong Antibody Response Seen in Patients With AML and MDS After Second Dose of mRNA COVID-19 Vaccine

Abstract 217: Responses to SARS-Cov-2 Vaccines in Patients with Myelodysplastic Syndrome and Acute Myeloid Leukemia

In one of the largest studies to date of the antibody response to vaccination against COVID-19 in people who had been treated for acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), patients responded well to two doses of the Moderna mRNA vaccine and saw a particularly dramatic increase in levels of antibodies against the virus after receiving their second vaccine dose.

We observed a strong antibody response to the vaccine in a group of patients at high risk for severe COVID-19, including among patients who were on active treatment for AML or MDS, said Jeffrey Lancet, MD, of the H. Lee Moffitt Cancer Center and Research Institute in Florida. The fact that antibody levels increased so dramatically after the second vaccine dose suggests potential utility in additional dosing, even for patients who initially respond poorly to the vaccine.

Previous studies had shown that patients with other types of blood cancer specifically, B-cell lymphomas or chronic lymphocytic leukemia often have a poor antibody response to vaccination with one of the COVID-19 mRNA vaccines. Treatment of these cancers suppresses the ability of the immune system to produce white blood cells such as B cells and T cells to fight off infection.

The treatment of myeloid cancers such as AML and MDS, including allogeneic transplantation, also suppresses white blood cells and leaves patients vulnerable to infection, said Dr. Lancet. We conducted this study to find out whether patients with these cancers would also have a suppressed or absent immune response to COVID-19 vaccination.

The study involved 46 patients who either had previously or were currently undergoing treatment for AML or MDS. The patients median age was 68 years; 59% were male and 96% were white. On average, they were about two years out from the diagnosis of their cancer. Fifteen patients (33%) were receiving treatment for their cancer at the time they were vaccinated. Thirty-two patients (70%) had undergone a transplant of blood-forming stem cells from a healthy donor as part of their cancer treatment. Forty patients (87%) were in remission when they were vaccinated. (Note that some patients are counted twice e.g., if they had undergone a stem cell transplant and were in remission, they would be counted in both categories. For this reason, the percentages add up to more than 100%.)

All patients received a first dose of the Moderna mRNA vaccine (this vaccine type was being given at the clinic) in late January 2021 and a second dose four weeks later. The investigators collected blood specimens from each patient before each vaccine dose was administered and again at four weeks after the second dose. The primary aims of the study were to describe the immune response and assess the safety profile of the vaccine in a cohort of patients with AML or MDS.

Blood test results at 29 days after the first vaccine dose showed that 70% of patients had an antibody response; at 57 days following the second dose 97% had an antibody response. Antibody levels were significantly higher after the second dose compared with after the first dose. Patients antibody response was not significantly affected by age, gender, race, disease status (i.e., active or in remission), time from disease diagnosis to vaccination, number of treatments patients had undergone for their cancer, whether patients had received a stem cell transplant, or whether they were on active treatment at the time of vaccination.

The most common adverse events following vaccination were the typical ones reported after vaccination with a COVID-19 mRNA vaccine, such as fatigue, headache, arm swelling, and mild pain at the injection site.

The study results should be confirmed in a larger group of patients, Dr. Lancet said. However, based on these data, we feel comfortable advising patients with AML or MDS that they should get vaccinated against COVID-19. Due to their vulnerability to COVID-19, they stand to benefit from the vaccine more than most.

This is an observational study without an identified control, or comparator, group, Dr. Lancet cautioned. Another limitation is that because the participants were overwhelmingly white, it is not known whether patients of other races or ethnicities would show a similar antibody response. In addition, the actual protective effect of the vaccine and the T-cell responses to it in this patient population are not yet known; the researchers are currently gathering these data.

The investigators are now following the same cohort of patients to determine whether a third dose of the vaccine can achieve even higher antibody levels than were seen after the second dose.

This press release was published by the American Society of Hematology on December 11, 2022.

Read more:
COVID-19 Takes a Toll on People with Blood Cancers and Disorders - Cancer Health Treatment News

Bristol Myers Squibb exec on the companys growth in Seattle and beating cancer with immune cells – GeekWire

BMS inherited Junos headquarters in Seattles South Lake Union neighborhood. (BMS Photo)

Pharmaceutical giant Bristol Myers Squibb has been quietly growing in the Seattle area.

Since acquiring Celgene and its Seattle operations two years ago, BMS now has more than 1,240 employees in the region, hundreds more than when the deal was announced.

BMS brings big pharma clout and a chunk of its $9.2 billion annual R&D budget to Seattles prospering biotech ecosystem, where global drug anchor companies have been as rare as bigfoot since Amgen shut down its Seattle hub five years ago.

Only Bothell, Wash.-based Seagen, with more than 2,500 employees worldwide, may top BMS in size among biopharma companies in the Seattle area. BMS has more than 150 open positions in the region, jostling with Sana Biotechnology, Umoja Biopharma and other cell and gene therapy biotech companies for workers.

BMS Seattle-area outpost, devoted to cell therapy and immuno-oncology, is one of about a dozen BMS R&D centers worldwide. Seattle BMS scientists are developing new ways to attack tumors by harnessing cells of the immune system and they are improving on two CAR T cellular therapies approved for certain blood cancers, Breyanzi and Abecma.

Breyanzi emerged from research at Seattles flagship cell therapy biotech company, Juno Therapeutics, which Celgene acquired in 2018 in a multi-billion dollar deal. BMS continues partnerships that Juno forged with Fred Hutch and Seattle Childrens Research Institute when Juno spun out of these institutions, and it is building new biotech collaborations to develop the next generation of therapies.

Leading BMS Seattle effort is Teresa Foy, who previously helmed Seattles Celgene operations and rose up through the ranks as an executive at two small Seattle biotech startups, VLST Corp and Oncofactor.

Our presence here is strong, Foy told GeekWire in an interview. Were hiring and were growing.

BMS footprint in the region includes a 266,000 square foot Seattle R&D facility built by Juno, and a manufacturing facility in Bothell, where the company manufactures Breyanzi.

The Seattle operation oversees clinical trials for Breyanzi and other cell therapies. BMS, for instance, aims to expand the eligible patient group for Breyanzi, which is currently approved for adults with certain types of lymphoma who have relapsed or do not respond after two front-line therapies. BMS recently released data in support of expanding the therapy to patients at an earlier stage of treatment.

BMS aims to reduce the steep cost of manufacturing CAR T cells, which involves engineering a patients own cells to attack their tumor. One option is to instead enable off-the-shelf therapies, derived from healthy donor cells or even stem cells.

The next generation of cellular therapies are also being built in Seattle. The company is engineering CAR T cells to overcome a hostile tumor environment and to recognize more than one molecular target. Such research aims to counteract the development of resistance to treatment and expand the therapy to solid tumors. BMS is also advancing TCR-engineered T cells which can target molecules inside tumor cells, not just on the cell surface as with CAR T cells.

Meanwhile, BMS is looking beyond cellular therapies at immune cell engagers. These are agents that interact with immune cells and direct them to recognize and attack cancer cells. BMS is testing such agents in phase 1 clinical trials for blood cancers and solid tumors.

Other cell and immune therapy companies pursue similar aims, but BMS brings multiple research strategies under one roof, bolstered by its strong clinical and manufacturing capabilities and web of academic and industry collaborations.

We talked with Foy about the companys growth and its vision for treating cancer with the immune system.

The interview with Foy below has been edited for clarity and brevity.

GeekWire: What do you think has kept BMS in the Seattle region?

Bristol Myers Squibb executive Teresa Foy: With the acquisition, BMS hired Celgene president Rupert Vessey as its president of research and early development. They really liked his research model, and BMS needed a kind of refresh on their research strategy. Vessey had helped build a distributed research model, with different innovation hubs, and each of those hubs has a different area of focus.

Part of what BMS recognized in the acquisition was that this was an important concept to keep intact, not just for Seattle, but for the other hubs as well. That was not traditionally how BMS operated their research. They were very centrally located in New Jersey, but now theyve sort of embraced this model. It leverages different locations for hiring and also allows you to tap into the ecosystems of local regions for academic expertise, other small companies to partner with, as well as the talent.

BMS wants to maintain the core expertise thats here and the critical mass of people to do cell therapy development. It takes a while to build that expertise and depth of experience. Being able to retain that and grow that here in Seattle is a real strength for us.

How does the cell therapy ecosystem in Seattle bolster your work, and do regional companies benefit as potential collaborators?

Foy: We certainly have a lot of academic history here in Seattle with Seattle Childrens, with Fred Hutch, and we still maintain those relationships. The talent pool has been shared across the region, and thats great for the ecosystem in Seattle.

We have partnerships and equity investments in some of the local companies [BMS investments include Presage Biosciences, Zymeworks, Silverback Therapeutics, and Lyell Immunopharma, which are based in the Seattle area or have operations there]. But we dont currently have any large collaborations with any current [local] companies. Part of the reason is some of our programs are competitive with each other. The technology and innovation cycle is continuing and we continue to have discussions with Sana, Lyell and other new companies.

We have partnerships with people all over the country and all over the world. But Seattle is a kind of center of excellence for cell therapies. Certainly, people around the country recognize that there was a strong foundation built here with Juno that expanded, and that has now seeded a bunch of new companies. I think thats an advantage for all of us because it brings talent here. It brings great scientific discussions and opportunity for collaboration.

Youre working in a field at the cutting edge of cancer research. What are you excited about for the future?

Foy: I do think that the progress will be exponential in the next five to 10 years because theres been so much innovation in technology and in bioinformatics, machine learning and artificial intelligence, which can help inform all the data that we gather from our patients. We can learn so much to feed back into improving the first generations of cell therapies. The technology is advancing things at kind of this frantic pace.

Im excited for us to be able to expand what weve learned in hematology, lymphoma and myeloma into solid tumors. And then well have to also apply what we learned in the immuno-oncology space with checkpoint inhibitors [immune modulating cancer drugs like BMS nivolumab]. What resistance mechanisms prevent checkpoint inhibitors from having longer effects or what prevents some patients from responding? Some of those same themes are holding true for cell therapies.

How are your research collaborations building the next generation of cellular therapies?

Foy: We have a partnership with Arsenal Bio, which is developing logic gates for solid tumors [enabling activation of therapeutic cells only within a tumor or under other conditions]. Obsidian therapeutics does regulated expression of proteins were adding particular proteins to our cell therapies that we can regulate to turn on just when we want them to, primarily for solid tumors to overcome tumor environment challenges. And then we have a partnership with Immatics, which has identified engineered T cell receptors to solid tumor targets, and were putting those in our in our cell therapies. So, theres lots going on with the next generation.

Were working on a couple of different approaches for off-the-shelf cell therapies. Allogeneic approaches [therapies from donor cells] are in the queue for both CD19 and BCMA [the targets of Breyanzi and Abecma]. And then a long ways off, were looking at other things like iPSC [stem-cell] derived therapies. We dont yet have a partnership there, but were working on exploring that.

Can you tell us about your other research efforts?

Foy: About 30% of our portfolio is focused on immune cell engagers. Those complement the cell therapy modality. They have some advantages in that they could be off the shelf, maybe give access to more patients. But obviously, you cant engineer as many things into those biologics as you can into a cell therapy. So its kind of a nice breadth for our portfolio to have optionality with both of them.

Any highlights from your clinical programs?

Foy: Both CD19 and BCMA CAR T cells [Breyanzi and Abecma] are in a next generation of manufacturing. And those essentially have a similar design but a different manufacturing process [that enables cells to persist longer in the body]. We entered a CAR T cell against a novel target, GPRC5D, for multiple myeloma, and that is in phase 1 now. Behind that we have an ROR1 CAR T cell well be enrolling patients early next year for that program, and that will be in chronic lymphocytic leukemia initially and then solid tumors subsequent to that.

What has it been like for you moving from small biotech companies to Celgene and then BMS?

Foy: I grew up as a bench scientist and gradually became a leader and then a chief scientific officer. I thought, Im not sure Im going to like the big company, but I found that doing good science is doing good science, regardless of whether youre in a small company or a big company. But being able to have resources to do it really well, and to actually see patients benefit from it, that was a huge, rewarding part.

Any final words?

Foy: Were really excited about segueing into solid tumors in the next five to 10 years and also looking at ways to make these cell therapies more affordable and off-the-shelf donor-derived. I think thats really the next generation of where the cell therapies will go.

Were also really proud of the community outreach weve done and our STEM efforts in Washington state. They are a really important part of our mission here [BMS is involved in outreach programs at the Pacific Science Center and other efforts]. Our staff is really excited to help mentor and educate the next generation of young scientists and hopefully keep the Seattle and Washington state ecosystem thriving with scientists of the future.

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Bristol Myers Squibb exec on the companys growth in Seattle and beating cancer with immune cells - GeekWire

Upregulated expression of actin-like 6A is a risk factor | CMAR – Dove Medical Press

Introduction

Pancreatic cancer (PC) with high aggressiveness and malignancy has become an enormously common cancer of the digestive system during 10 years. Globally, the 5year overall survival (OS) rate of patients with PC is less than 9%, and the mortality rate is predicted to peak by 2030.1 Due to insidious symptoms, only less than 10% of PC is initially diagnosed with a local stage, and the prognosis of PC is extremely poor.2 Therefore, further investigation into novel cancer-related genes is required and meaningful for the improvement of prognosis.

SWI/SNF complexes are evolutionarily conserved multi-subunit molecular machines that mediate transcriptional regulation3 and are linked to a poor prognosis across several cancer types.46 Among them, Actin-like 6A (ACTL6A), encoded by Actl6a, acts as a chromatin-remodeling factor and regulates the function of progenitor and stem cell transcriptionally.7,8 In addition, ACTL6A expression is associated with prognosis in many types of cancer, such as hepatocellular carcinoma,9 colon cancer,10 and esophageal squamous cell carcinoma.11 Recently, research revealed that epithelial-to-mesenchymal transition (EMT) was also regulated by ACTL6A.9,12 In addition, the study showed that ACTL6A overexpression could lead to increased repair of cisplatin-DNA adducts and cisplatin resistance.13 However, the role of ACTL6A in tumorigenicity and clinical prognosis of PC remains unclear so far.

In this connection, we analyzed the differences of ACTL6A expression in PC tissues and normal tissues, and we investigated the prognostic effect of ACTL6A on PC based on cases in public databases and confirmed it in our center.

Differential expression of Actl6a mRNA between pancreatic tumor and normal tissues was analyzed using the Gene Expression Profiling Interactive Analysis website (GEPIA; http://gepia.cancerpku.cn/). Data for 179 patients with PC and 171 normal tissue samples analyzed on the GEPIA website were obtained from TCGA and normal tissue samples from Genotype-Tissue Expression (GTEx).1416 The gene expression, determined as transcripts per million (TPM), was calculated by log2 (TPM + 1) for comparison. Based on the expression levels of Actl6a mRNA, the overall survival (OS) of patients was also analyzed.

A total of 60 patients with PC confirmed by histopathology from January 2013 to June 2020 at Zhongda Hospital, Medical School of Southeast University were selected for the study. Sixty paired pancreatic tumor and normal tissues from patients who did not receive chemotherapy or radiotherapy were obtained to detect ACTL6A expression. Any patients with incomplete epidemiological and clinical information or lack of follow-up information were excluded. The results of serum tumor markers were collected from 60 healthy individuals who were admitted to the hospital for physical examination at the same time. All patients provided informed consent. Patients were followed up by telephone or at office visits every 3 months from the end date of surgery. The latest follow-up ended in July 2021. According to the eighth edition of the American Joint Committee on Cancer (AJCC) Cancer Staging Manual, pathological stages were validated. The study was conducted with approval from the ethics committee of Zhongda Hospital, Southeast University. The study protocol protected the private information of enrolled patients in accordance with the provisions of the Helsinki Declaration.

The paraffin-embedded pathological specimens were cut into 4-m-thick sections. After being dewaxed in xylene and rehydrated in grade alcohol, the paraffin sections were submerged in a pH 6.0 citric acid solution and heated at 95C for approximately 15 minutes for antigen retrieval. Next, the sections were incubated with rabbit ACTL6A antibody (Abcam Corp, USA, diluted 1:200) overnight at 4C and washed 3 times with phosphate buffer saline (PBS). The sections were then incubated with horseradish peroxidase-conjugated secondary antibody for 30 minutes at room temperature in the dark. After stained with freshly prepared 3,3-diaminobenzidine (DAB), they were counterstained with hematoxylin and differentiated with 1% hydrochloric acid. PBS was used to substitute the primary antibody as negative control. Finally, the sections were dehydrated with alcohol and sealed with neutral gum, and pictures were taken by microscope for positive cell calculation. Immunohistochemical staining analysis was performed independently by two pathologists according to the staining intensity and the percentage of positive cells. The staining intensities were 0 (negative), 1 (positive 1+), 2 (positive 2+), and 3 (positive 3+), respectively. The percentages of cells were 0 (negative), 1 (125%), 2 (2650%), 3 (5175%), and 4 (76100%), respectively.17,18 Total scores were calculated by multiplying the scores of staining intensity and percentage.

Statistical analyses and mapping were performed using SPSS software (version 18.0, IBM Corporation, Armonk, NY, USA), GraphPad Prism (Version 8.4.3, GraphPad Software, La Jolla, CA, USA), and R (version 3.4.1, http://www.r-project.org/) in the present study. Wilcoxon test was used to evaluate significant differences between pancreatic cancer and normal tissues, and the 2 test and continuity correction were used to explore the relationship between ACTL6A expression and clinicopathological features. The diagnostic efficiency of ACTL6A expression was analyzed through receiver operating characteristic (ROC) curves for PC. The sensitivity and specificity were evaluated at an optimal cutoff. The expression of ACTL6A was classified as high expression and low expression according to the cutoff. Survival analysis was analyzed using KaplanMeier curve, and difference among groups was assessed using Log rank test. Both univariable and multivariable analyses were used in survival analysis, respectively. The clinicopathological factors with significant associations (p < 0.1) in the aforementioned univariable analysis were subjected to multivariate analysis. p < 0.05 was considered to be statistically significant.

To explore the potential role of ACTL6A in PC, the expression of Actl6a mRNA was analyzed with the publicly available GEPIA database. In clinical PC specimens (n = 178) and normal tissues (n = 171), Actl6a mRNA had significant differential expression between the two groups. What is more, Actl6a mRNA was upregulated in PC than normal tissues (p < 0.05, Figure 1A). Then, the protein expression of ACTL6A was validated and compared in PC samples (n = 60) and normal tissues (n = 60) with immunohistochemistry staining in our center. The typical immunohistochemical results of normal tissues and PC tissues are shown in Figure 1B, which demonstrated that ACTL6A was mainly observed in the nucleus of cells. By multiplying the staining intensity and percentage, the protein expression of ACTL6A was also overexpressed in pancreatic cancer (p < 0.001, Figure 1C). Table 1 shows the number of patients with different scores based on immunohistochemistry staining. The results above indicated that ACTL6A was upregulated in PC.

Table 1 The Number of Patients in Different Scores Based on Immunohistochemistry Staining

Figure 1 Expression of ACTL6A in PC and normal tissues. (A) Differential expression of Actl6a mRNA between pancreatic tumor and normal tissues. (B) Immunohistochemical results of typical normal tissues and PC tissues with different staining intensities. (C) Differential expression of ACTL6A between pancreatic tumor and normal tissues. (D) ACTL6A represented a moderate diagnostic value. The ROC of pancreatic cancer samples and normal tissues. (E) ROC for the diagnostic efficiency of ACTL6A, serum CEA, and serum CA199. *p<0.05.

Abbreviations: ACTL6A, actin like 6A; PC, pancreatic cancer; ROC, receiver operating characteristic curves; CA199, carbohydrate antigen 199; CEA, carcinoembryonic antigen.

To investigate the diagnostic value of ACTL6A expression for PC, we performed ROC analysis on total scores of pancreatic cancer and normal pancreatic tissue, as shown in Figure 1D and E, and the AUC value was 0.724, which was higher than that of carbohydrate antigen 199 (CA199) and carcinoembryonic antigen (CEA). These results represented a moderate diagnostic value for PC. The specificity and sensitivity of ACTL6A expression for PC diagnosis were 0.867 and 0.567, respectively. The cut-off value established for ACTL6A expression for the diagnosis of PC was 5.

To further understand the role of ACTL6A in PC, we analyzed the relationship between ACTL6A expression and the clinicopathological characteristics. Patients with PC were divided into ACTL6A low-expression group (score 05; n = 34) and ACTL6A high-expression group (score 612; n = 26) with the cut-off value of score 5. The relationship between ACTL6A expression and clinicopathological factors of pancreatic cancer is summarized in Table 2. Lymphovascular space invasion (LVSI) of PC was significantly associated with ACTL6A expression, which was more likely to occur in the ACTL6A high group. LVSI was present in 55.9% (19/34) of patients in the ACTL6A high group and 26.9% (7/26) in ACTL6A low group.

Table 2 Relationships Between the Expression Level of ACTL6A and the Clinicopathological Characteristics of PC Patients

The survival data of 178 PC patients was obtained from TCGA dataset. Patients are split into two groups according to the median value of Actl6a mRNA expression. One-half (89 patients) was defined as high Actl6a mRNA expression, and the other was defined as low Actl6a mRNA expression. Obviously, high Actl6a mRNA was associated with poor overall survival in patients with PC (p < 0.001, Figure 2A). Furthermore, based on data from our center, the KaplanMeier method was used to investigate the relationship between the expression of ACTL6A protein and OS of patients. The median OS in PC patients for the high and low expression of ACTL6A was 8.0 0.4 months and 13.0 1.6 months, respectively. Obviously, patients with low ACTL6A expression had significantly longer survival time than those with high ACTL6A expression (p < 0.001, Figure 2B).

Figure 2 (A) KaplanMeier curves of overall survival in PC patients with high and low Actl6a mRNA expression. (B) KaplanMeier curves of overall survival in PC patients with high and low ACTL6A expression.

Abbreviations: ACTL6A, actin like 6A; PC, pancreatic cancer.

Univariate and multivariate Cox analyses were performed to identify the prognostic factors on OS of patients with PC. The results demonstrated that ACTL6A overexpression (p = 0.032) and grade (p = 0.008) were risk factors for survival in patients with PC through univariate Cox analysis. Further multivariate Cox analysis showed that ACTL6A expression (p = 0.046) was an independent risk factor for poor prognosis of PC (Table 3). As shown in Figure 3A and B, the forest plot visualizes the specific HR of risk factors.

Table 3 Univariate and Multivariate Analysis of Clinicopathological Characteristics Affecting Prognosis of Patients with PC

Figure 3 Forest plot of univariate (A) and multivariate (B) cox regression.

Abbreviations: ACTL6A, actin like 6A; PC, pancreatic cancer; LVSI, lymphovascular space invasion.

Worldwide, PC has become a malignancy with a dismal prognosis and high mortality, which has a 5-year survival rate of less than 10%.19 There are two clinical features that are involved with the poor prognosis of PC. First, initial symptoms of PC are insidious, which leads to many challenges for early diagnosis. Second, PC has a significant potential for invasion and metastasis.20 In detail, the distant spread may occur in the early stages of PC, and more than 50% of patients with PC have no possibility to be treated with surgical resection.21 Scientific problems covering early diagnosis, the mechanisms of metastasis, and the risk factors of prognosis are necessary to be solved to improve survival of PC. In this study, we clarified that ACTL6A is highly expressed in PC, and it is a reliable marker for predicting the prognosis of PC patients.

ACTL6A is involved in a variety of cellular processes, including vesicle transport, spindle orientation, nuclear migration, and chromatin remodeling.7,22 Increasing evidence has suggested its involvement with tumorigenesis and development of cancer.7 ACTL6A has been reported to be overexpressed in a variety of malignancies, including hepatocellular carcinoma,9 ovarian cancer,18 cervical cancer,23 and esophageal squamous cell carcinoma,11 which is correlated with the prognosis of patients with malignancies. This evidence suggests that ACTL6A is a potential oncogene, and it is observed that ACTL6A expression is also upregulated in PC in our study, which is consistent with previous studies. Researchers have been constantly exploring diagnostic markers for PC. Jelski et al reported that the activity of alcohol dehydrogenase (ADH) class III isoenzyme in pancreatic cancer was significantly higher than that in normal tissues.24 And the total activity of ADH and class III isoenzyme was increased in the serum of patients with PC, which can be due to the release of this isoenzyme from PC cells.25 Nevertheless, it was not observed that other types of ADH isoenzymes (I, II, IV) had a significant change in either pancreatic tissue or serum. Further exploration revealed that ADH III had the diagnostic value for PC.26 Also, our evidence demonstrated a potential role for ACTL6A as a marker of PC.

ACTL6A plays a vital role in the invasion and metastasis of tumors by promoting EMT, leading to poor prognosis. ACTL6A expression is higher in fibroblasts and progenitor cells and inhibits the epithelial properties of epidermal tissues.27,28 Moreover, the functions of ACTL6A are similar to features of stem cells, including the inhibition of cell differentiation and the ability of self-renewal, which is closely related to the biological functions of EMT.28 In hepatocellular carcinoma, ACTL6A activated Notch1 signaling via SOX2, which regulated EMT to affect the biological function and clinical prognosis of hepatocellular carcinoma. Other studies also revealed ACTL6A as an EMT activator to promote metastasis in osteosarcoma29 and colon cancer,10 respectively. Some studies mentioned the potential role of ACTL6A involvement with tumors. Zhang et al found that ACTL6A was a glycolytic regulator by phosphoglycerate kinase 1(PGK1) in ovarian cancer and participated in FSH-induced tumorigenesis of ovarian cancer.18 And in triple negative breast cancer, ACTL6A promoted tumor cell proliferation by enhancing the stability of MYC oncogene.30 Additional evidence suggested that ACTL6A promoted the progression of cervical cancer and laryngeal squamous cell carcinoma through activation of yes-associated protein (YAP) signaling.23,31 Besides, ACTL6A could stabilize transcriptional regulators YAP and transcriptional coactivator with PDZ-binding motif (TAZ) to regulate the proliferation, migration, and invasion of glioma.32 Further studies revealed that the knockdown of ACTL6A gene resulted in the inhibition of protein kinase B (AKT) signaling pathway to suppress cell migration and increased sensitivity of glioma cells to temozolomide.33 Moreover, in vivo and in vitro, Shrestha et al revealed that p21Cip1, a tumor suppressor, was suppressed by ACTL6A in epidermal squamous cell carcinoma, leading to epidermal squamous cell carcinoma progression.34 More importantly, overexpressed ACTL6A was related to cisplatin-induced DNA damage and led to resistance to cisplatin.13 These studies have further confirmed the contribution of ACTL6A in the invasion, metastasis, and clinical prognosis of tumors.

In this research, we reveal a correlation between the expression of ACTL6A and the invasion and prognosis of PC. It was found that LVSI was more likely to occur in PC patients with high ACTL6A expression, which might be related to the high aggressiveness caused by ACTL6A. Univariate and multivariate Cox analysis suggested that ACTL6A expression and grade were independent risk factors for poor prognosis of PC. This study also confirmed ACTL6A as a valid prognostic biomarker and potential therapeutic target in PC. Given a follow-up and survival analysis of survival data of PC patients, patients with high ACTL6A expression had significantly poorer prognosis. It was suggested that ACTL6A expression in PC was a risk factor, which was consistent with the existing studies. And ACTL6A overexpression was associated with tumor progression. However, whether ACTL6A could induce PC cell proliferation, invasion, and metastasis in vitro, as well as the specific regulatory mechanisms, deserved further investigation.

In conclusion, it was found that levels of ACTL6A expression were elevated in PC tissues, which was associated with LVSI. Moreover, it was demonstrated that ACTL6A was an independent risk prognostic indicator for PC. ACTL6A could be used as a valuable biomarker to predict the prognosis of PC, assisting clinicians to develop preventative measures and better treatment strategies to improve mortality in patients with PC.

The authors are grateful to all the patients, researchers and institutions that participated in the TCGA and GTEx database.

The authors report no conflicts of interest in this work.

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18. Zhang J, Zhang J, Wei Y, Li Q, Wang Q. ACTL6A regulates follicle-stimulating hormone-driven glycolysis in ovarian cancer cells via PGK1. Cell Death Dis. 2019;10(11):811.

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21. Lamb YN, Scott LJ. Liposomal irinotecan: a review in metastatic pancreatic adenocarcinoma. Drugs. 2017;77(7):785792.

22. Zhao K, Wang W, Rando OJ, et al. Rapid and phosphoinositol-dependent binding of the SWI/SNF-like BAF complex to chromatin after T lymphocyte receptor signaling. Cell. 1998;95(5):625636.

23. Zhao J, Li L, Yang T. MiR-216a-3p suppresses the proliferation and invasion of cervical cancer through downregulation of ACTL6A-mediated YAP signaling. J Cell Physiol. 2020;235(12):97189728.

24. Jelski W, Chrostek L, Szmitkowski M. The activity of class I, II, III, and IV of alcohol dehydrogenase isoenzymes and aldehyde dehydrogenase in pancreatic cancer. Pancreas. 2007;35(2):142146.

25. Jelski W, Zalewski B, Szmitkowski M. Alcohol dehydrogenase (ADH) isoenzymes and aldehyde dehydrogenase (ALDH) activity in the sera of patients with pancreatic cancer. Dig Dis Sci. 2008;53(8):22762280.

26. Jelski W, Kutylowska E, Laniewska-Dunaj M, Szmitkowski M. Alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) as candidates for tumor markers in patients with pancreatic cancer. J Gastrointestin Liver Dis. 2011;20(3):255259.

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28. Lu W, Fang L, Ouyang B, et al. Actl6a protects embryonic stem cells from differentiating into primitive endoderm. Stem Cells. 2015;33(6):17821793.

29. Sun W, Wang W, Lei J, Li H, Wu Y. Actin-like protein 6A is a novel prognostic indicator promoting invasion and metastasis in osteosarcoma. Oncol Rep. 2017;37(4):24052417.

30. Jian Y, Huang X, Fang L, et al. Actin-like protein 6A/MYC/CDK2 axis confers high proliferative activity in triple-negative breast cancer. J Exp Clin Cancer Res. 2021;40(1):56.

31. Dang Y, Zhang L, Wang X. Actin-like 6A enhances the proliferative and invasive capacities of laryngeal squamous cell carcinoma by potentiating the activation of YAP signaling. J Bioenerg Biomembr. 2020;52(6):453463.

32. Ji J, Xu R, Zhang X, et al. Actin like-6A promotes glioma progression through stabilization of transcriptional regulators YAP/TAZ. Cell Death Dis. 2018;9(5):517.

33. Chen X, Xiang Z, Li D, Zhu X, Peng X. ACTL6A knockdown inhibits cell migration by suppressing the AKT signaling pathway and enhances the sensitivity of glioma cells to temozolomide. Exp Ther Med. 2021;21(2):175.

34. Shrestha S, Adhikary G, Xu W, Kandasamy S, Eckert RL. ACTL6A suppresses p21(Cip1) expression to enhance the epidermal squamous cell carcinoma phenotype. Oncogene. 2020;39(36):58555866.

Link:
Upregulated expression of actin-like 6A is a risk factor | CMAR - Dove Medical Press