Category Archives: Stem Cell Treatments

Whether a patient is refractory to initial treatment dictates the future course of care.

The multitude of options to treat multiple myeloma (MM) doesnt change an important fact: the duration of a patients response to the first treatment will define the disease biology going forwardhow well the disease is managed in the early going matters, according to Shaji K. Kumar, MD, of the Mayo Clinic Cancer Center, who gave an update on MM management during Fridays National Comprehensive Cancer Center (NCCN) annual meeting.

Fortunately, results from the GRIFFIN trial are showing whats possible. Results presented at the December 2021 meeting of the American Society of Hematology showed positive outcomes after 24 months for newly patients who took quadruplet therapy after an autologous stem cell transplant (ASCT). The combination, which added daratumumab to the usual combination of lenalidomide, bortezomib, and dexamethasone (RVd) had better stringent complete responses (sCR, 66.0% vs 47.4%), along with higher minimal residual disease (MRD) negativity rates.

This clearly appears to be translating into an improvement in progression-free survival (PFS), Kumar said. Its too soon to start treating every patient with newly diagnosed, transplant-eligible MM this way, but given the high rates of MRD negativity that we see with Dara-RVd, this regimen is definitely one to consider for patients with high risk multiple myeloma.

What about patients who are not transplant eligible, or need to wait? The IFM 2009 study compared giving ASCT right away with additional doses of therapy. Although ASCT clearly offered better PFS, there was not improvement in overall survival (OS), Kumar noted. Thus, it is very reasonable to delay stem cell transplant to the time of first relapse.

For these patients, daratumumab with lenalidomide and dexamethasone should be considered the standard, based on the MAIA study, he said.

Ongoing treatment. After initial treatment and lenalidomide maintenance, treatment choices are driven by whether patients are refractory to lenalidomide, Kumar explained. He shared a slide with multiple doublet and triplet options, and explained that triplets are now preferred, with one drug being dexamethasone. Prior treatments, age, comorbidities, frailty, and any lingering toxicity should be considered.

In general, the approachespecially in the earlier lines of therapyis to treat patients to maximum response, and then maintain them on at least one of the drugs from the combination until disease progression, Kumar said. This is easier in the early lines of therapy, he acknowledged. Whether a patient is refractory on their initial therapy is a key differentiator is a key differentiator that guides treatment going forward.

Selinexor, an XP01 inhibitor, was approved in December 2020 for use with bortezomib and dexamethasone in patients who have had at least one prior therapy. Belantamab mafodotin, is an antibody drug conjugate that targets B-cell maturation antigen (BCMA), and could be used to treating patients that have been refractory to other major drug classes, including protease inhibitors. Long-term data from the DREAMM-2 study found that median duration of response, OS, and PFS were 11.0 month, 13.7 months, and 2.8 months.

A recent highlight is the FDA approval last month of a second chimeric antigen receptor (CAR) T-cell therapy for MM, ciltacabtagene autoleucel (cilta-cel) which also targets BCMA. In the CARTITUDE trial, results at 2 years showed median PFS and OS were not reached and sCR was 82.5%.

Kumar also reported on several clinical trials involving investigational therapies and new uses of existing therapies, including:

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Early Treatment Matters More Than Ever in Multiple Myeloma, Kumar Says - AJMC.com Managed Markets Network

This article was originally published here

Stem Cell Res Ther. 2022 Mar 24;13(1):124. doi: 10.1186/s13287-022-02810-6.

ABSTRACT

The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has spread into more than 200 countries and infected approximately 203 million people globally. COVID-19 is associated with high mortality and morbidity in some patients, and this disease still does not have effective treatments with reproducibly appreciable outcomes. One of the leading complications associated with COVID-19 is acute respiratory distress syndrome (ARDS); this is an anti-viral host inflammatory response, and it is usually caused by a cytokine storm syndrome which may lead to multi-organ failure and death. Currently, COVID-19 patients are treated with approaches that mostly fall into two major categories: immunomodulators, which promote the bodys fight against viruses efficiently, and antivirals, which slow or stop viruses from multiplying. These treatments include a variety of novel therapies that are currently being tested in clinical trials, including serum, IL-6 antibody, and remdesivir; however, the outcomes of these therapies are not consistently appreciable and remain a subject of debate. Mesenchymal stem/stromal cells (MSCs), the multipotent stem cells that have previously been used to treat viral infections and various respiratory diseases such as ARDS exhibit immunomodulatory properties and can ameliorate tissue damage. Given that SARS-CoV-2 targets the immune system and causes tissue damage, it is presumable that MSCs are being explored to treat COVID-19 patients. This review summarizes the potential mechanisms of action of MSC therapy, progress of MSC, and its related products in clinical trials for COVID-19 therapy based on the outcomes of these clinical studies.

PMID:35321737 | DOI:10.1186/s13287-022-02810-6

Link:
Mesenchymal stem/stromal cell therapy for COVID-19 pneumonia: potential mechanisms, current clinical evidence, and future perspectives - DocWire News

Medulloblastomas are classified as WHO grade IV malignant tumors occurring primarily in the cerebellum in pediatric patients; they vary in prognosis depending on the subtype of the tumor. Usually occurring in children under 16, a large majority of patients are under 10 [1].

Pediatric populations diagnosed with medulloblastomas comprise 15%-20% of all brain tumors [2]. Unfortunately, the quality of life for many of these children severely deteriorates despite high survival rates with aggressive chemotherapy, radiotherapy, and neurosurgery [3]. Due to the prevalence of medulloblastomas situated in the posterior fossa, they often rapidly metastasize into the cerebrospinal fluid and affect different parts of the brain, aside from the infratentorial region [4]. Surgical intervention can delay the metastasis of medulloblastomas; however, one or more neurological impairments are a common side effect in 25% of the population. Unfortunately, a familiar condition is posterior fossa syndrome which interferes with communicative activities and manifests into ataxiaand hypotonia[5]. Thus, it has become imperative to assess combination therapies that may be used alongside traditional treatment protocols to delay treatment in younger children until they are three and thereby reduce neurological impairment.

The current treatment strategy for medulloblastomas, in children under three, consists primarily of surgery and chemotherapy and yields beneficial results in effectively reducing tumors. The best outcome has been observed with wingless (WNT)-activated medulloblastomas in the cohort of children under 16, but that statistic does not apply to children under five. However, for some subtypes of medulloblastoma, there remain high rates of diffuse metastasis [6]. Treatment in these aggressive situations results in a reduction in quality of survival for patients in terms of decreased intelligence quotient, while neuroendocrine side effects (i.e. growth hormone deficiency and hypothyroidism) generate a necessity for chronic symptomatic treatment [7]. Additionally as previously mentioned, ataxia and hypertonia can be side effects that will generate further medical complications requiring physical therapy, reduced muscle function, and difficulty in performing involuntary actions like swallowing. In this review, we initially focus on the subtypes of medulloblastomas and then review current treatment options, including immunotherapy, stem cell therapy, and pharmacological compounds.

Medulloblastoma tumors are categorized into four subgroups by the Cancer Genome Atlas (WNT, sonic hedgehog (SHH), group 3, and group 4); in spite of current treatments, 30% of patients have a relapse which portends a poor outcome [8].Any current treatment regimen is not equally effective against the different subgroups of medulloblastoma, and patients that survive past five years may face a recurrence of the disease [9]. Novel treatments are required for individualized subtypes of medulloblastomas since current protocols generalize patients with a similar treatment plan and leave patients with degenerative conditions as a result of long-term treatment toxicity [10].

Group 4

Group 4 medulloblastomas are the most common type and it is prevalent in males three times more frequently than in females [11]. Group 4, SHH-group, and group 3 tumors tend to originate from the intermediary area under the vermis of the cerebellum. Despite its frequency in patients, it is difficult to treat because the tumor metastasizes prior to diagnosis in 30%-40% of patients, which contributes to a low five-year survival rate of 60% [12,13]. Patients with group 3 tumors constitute a high-risk group compared to other sub-types as subtotal resection of the tumor during surgery increases the risk of disease progression, complicating the benefit of gross total or near-total resection [14]. Group 4 tumors have a high rate of recurrence as 30%-40% of patients are at high risk and the five-year survival for children is 60% while for adults there is a high degree of variability with a five-year survival between 45%-75% [15]. The 10-year survival rate is 36% for high-risk group four patients while for low-risk patients it is 72% and this is characterized by their chromosome 11 loss[16].

SHH-Group

SHHgroup medulloblastomas occur in both infants and adults and are the second most common subgroup. Treatment is a challenge because radiotherapy is highly debilitative in infants under 36 months and adults have a recurrence rate of 50%-60%, regardless of treatment intervention [17, 18]. Adults make for difficult patients to treat as their medulloblastoma genomic profiles are very different in adult medulloblastomas and there is a connection between the amplification of CDK6 and rapidly terminal outcomes [19]. Due to the rarity of adult cases, pediatric regimens tend to be used as treatment protocol and prognosis is not ideal. SHH group tumors are conventionally found in the posterior fossa of the brain in the cerebral hemispheres [20]. This is due to SHH signaling being part of the morphogenesis and maintenance of neurons that form both hemispheres of the brain [21]. SHH-group medulloblastomas tend to happen in infants, and the 10-year survival rate for infants is 77%, children have around 51% success, while for adults it is 35% [22].

Group 3

Group 3 tumors are the most aggressive and metastatic of the sub-types due to the amplification of the MYC gene, which causes tumorigenesis [23-25]. Unfortunately, due to the prognosis of this disease, outside of the conventional treatment of surgery and chemotherapy, there have yet to be targeted treatments developed for group 3 due to the heterogeneity in the nature of tumor recurrence [26]. Current treatments also include craniospinal irradiation for high-risk patients like those with group 3 medulloblastomas, but due to the slowed progression to metastasis, they can be ineffective [27]. 35%-45% of initial group-3 medulloblastoma survivors experience fatal relapse [28]. The 10-year survival rate for this medulloblastoma in infants is 39% and in children, it is 50% [29].

WNT-Group

WNT-activated medulloblastomas have the best prognosis of all the sub-groups; however, they are the least common type of medulloblastoma [30]. WNT signaling, especially when canonical, is associated with many types of cancers [31]. Due to its prevalent nature, the signaling pathway of WNT-activated tumors and metastatic cancers has been thoroughly researched to discover its role in immune evasion. Aberrations in the WNT pathway (i.e., hyperactivation of WNT resulting in medulloblastoma tumors) result in an ideal tumor microenvironment as WNT ligands released by tumor cells bypass the host immune response [32]. Surgery and radiation tend to improve the prognosis for children towards a 10-year survival 95% when compared to the other subtypes of medulloblastomas [33].

Standard care of treatment is generally successful to some extent in patients with more common subtypes, and it is primarily a combination of surgery, radiotherapy, and chemotherapy. There are many clinical trials assessing the efficiency of combinations of currently approved treatments, but many patients are more interested in knowing about their clinical trial options, especially at the time of relapse.

For examining the current clinical trials for medulloblastomas, the US government clinical trials website (ClinicalTrials.gov) database was utilized and filtered using the following: medulloblastoma therapies, active, recruiting, enrolling by invitation, and completed studies. The inclusion criteria were comprehensive of both systemic therapies; radiation or surgery-based studies were also considered. Terminated, withdrawn, and unknown status studies were excluded. Of the 82 studies available for medulloblastomas, 32 matched the listed criteria. Treatments with preliminary or interim positive results were grouped based on the type of therapy and mechanisms of action; the preliminary results and the potential of the therapy for medulloblastomas were then summarized and discussed (Table 1).

Many of the oncolytic virus and vaccine immunotherapies with radiotherapy are still in the trial stage, but it seems that of the three categories, immunotherapies seem to be the future of medulloblastoma treatment [44]. There are many types of viruses that may initiate gliomas, and there is evidence suggesting that measles, myxoma virus, picornavirus, and cytomegalovirus can be involved in the case of medulloblastomas [45-48].

Natural killer cell therapy represents another type of immunotherapy that has been speculated to hold a strong potential for therapy due to strong in vitro results [49]. But the only trial available identified as NCT02271711 does not demonstrate or notify of any results related to the trial [50]. Another therapy, G207 HSV viral therapy or herpes viral therapy with radiation, identified as NCT02457845, demonstrated an increased count for lymphocytes targeting tumor cells. The therapy alone was not effective for aggressively chronic conditions, but combinations can be explored [51] (Table 2).

Autologous stem cell rescue (ASCR) therapy, different from induced pluripotent stem cell therapy, uses the patients blood stem cells to regrow bone marrow tissue. Usually, this method is used to combat the harsh results of chemotherapy as radiation tends to cause degradation of bone marrow. The efficiency of stem cells at this point in research tends not to provide significant results of progress and is often used in conjunction with other therapies [55](Table 3).

Many of the trials solely used one pharmacological compound paired with surgical resection and radiation therapy. The type of radiation therapy available at the location and time of the trials may have affected the results, but rather than that, combination therapies seemed to be ideal for some trials. The mechanism of many of the drugs targets SHH-subtype medulloblastomas and cannot be used in broad-spectrum therapies. For the increasing quality of life, donepezil seems to be a drug that may be useful for early intervention to delay symptoms in children under the age of five, however, the success of donepezil may be due to the combination with radiation. Donepezil is a cholinesterase inhibitor that increases the concentration of neurotransmitter acetylcholine in the brain, further inducing synaptic plasticity in the brain.Often relapses in WNT-activated medulloblastomas are a result of continuous aggressive treatment regimens which cause an accumulation of cyclophosphamide doses, but this is being improved with a stronger emphasis on abatement of both chemotherapy and radiation [83]. Other pharmacological interventions need to be used on a case-by-case basis to identify suitable or unsuitable combinations (Figure 1).

From analyzing the results and current statuses of clinical trials associated with functional medulloblastoma treatment, it is plausible to state that SHH-subtypes are the most targeted; recurrent medulloblastoma patients are also a target. Children under three tend to be neglected for treatment options as combination therapies with radiation provide ideal outcomes. Immunotherapies with combination treatments may be suitable for protocol treatments for patients with specific profiles, and pharmacological compounds or stem cell therapy may be potential treatment avenues with promising results when done with conventional surgical resection and radiation therapy. These treatment options may also allow for children under three to avoid radiation therapy until they are of age.

Many of the treatments and clinical trials aim to target a plethora of CNS tumors rather than specifically targeting medulloblastomas. This may be due to the rarity of the condition or the lack of participation from the small subset of patients in experimental clinical trials, but this reduces the overall specificity of treatment for different types of medulloblastomas. Many completed clinical trials also did not report their study results in the form of a publication or data in the clinicaltrials.gov website which may indicate unfavorable data results.

When comparing the studies, it is essential to realize that combination therapies hold the most promise in these experimental treatment plans. There are some forward therapies which are used in older populations like vismodegib and others which simply target the SHH-group medulloblastomas and that can be seen with CX-4945 and arsenic trioxide in addition to vismodegib for pharmaceutical therapies. Immunotherapy holds promise as there is a genetic component of medulloblastomas; training the innate system to destroy the cancer cells, in addition to surgical resection and adaptive radiotherapy, seems to hold the most potential for widespread intervention protocol development as they attempt to minimize the complications that many pharmaceutical reagents can bring. Donepezil may also be helpful in pediatric patients who require radiation minimization for the quality of future development, but radiotherapy becomes essential with any of the therapy options offered in trials.

It is important to investigate individualized treatment plans in reference to the sub-type of medulloblastoma targeted. Future studies should also be comprehensive of international clinical studies as many data-recording platforms are not translated or exclusively demonstrate national studies. Doing so would allow for more clinical trial options for patients and their families. Children who are medulloblastoma survivors have a severe need for symptomatic treatment to preserve their cognitive and neuroendocrine functions. Since the pertinent issue is increasing length of survival, there should also be trials investigating the quality of survival through methods of combating impaired cognition and reducing radiotherapy. Since medulloblastoma treatment, especially when recurring, is mainly focused on increasing the quality of living while extending life expectancy, there are caveats in available treatments; experimental therapy consent becomes a sensitive issue for families when treating children. Prospective successful treatments may be a combination of chemotherapy, radiation, and immunotherapy post-surgical resection and the combination of chemotherapy and immunotherapy could be a sustained solution for children without radiation. This would allow many medulloblastoma survivors to have a more cognizant and independent experience of living as their developmental functions would not be toxically affected.

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A Holistic Review on the Current and Future Status of Biology-Driven and Broad-Spectrum Therapeutic Options for Medulloblastoma - Cureus

Mantle cell lymphoma is a difficult cancer type with high relapse rates, but novel targeted approaches such as CAR T-cell therapy hold promise for more successful response rates in the future.

First-line treatment strategies for mantle cell lymphoma (MCL) currently range from intensive chemotherapy and autologous stem cell transplant (ASCT) to combination regimens and novel targeted therapies. As chimeric antigen receptor (CAR) T-cell therapies change the treatment landscape in other hematological cancer types, a recent review sees potential for this novel strategy to improve outcomes for MCL.

MCL is a B-cell malignancy that is rare and challenging to treat, and relapse rates are high. In most cases of MCL, the chromosomal translocation t(11;14) causes overexpression of thecyclin D1 (CCND1) gene, although other mechanisms are also involved. Despite progress in identifying the pathogenesis and risk factors of MCL, there are still no curative treatments for it.

In the first-line setting, the current standard treatment for otherwise healthy younger patients is intensive immunochemotherapy, potentially followed by ASCT to improve response duration. Older patients who cannot tolerate intensive treatment typically undergo treatment with more tolerable combination regimens.

When patients relapse, targeted agents are generally used in lieu of the chemoimmunotherapy seen in first-line treatment. Initially, bortezomib, temsirolimus, and lenalidomide were the only approved targeted second-line treatments, but the current treatment landscape also includes agents such as Bruton tyrosine kinase (BTK) inhibitors, BCL2 inhibitors, lenalidomide, and venetoclax. Three BTK inhibitors ibrutinib, acalabrutinib, and zanubrutinib are currently approved for relapsed or refractory MCL.

Response rates have been promising with targeted therapies, but response durations are often limitedand even on these regimens, many patients relapse. In patients with known risk factors such as TP53aberrations, high Ki-67, or those whose disease progresses on BTK inhibition, treatment is even more challenging and novel approaches must be identified to improve outcomes.

In recent years, CAR T-cell therapy has emerged as a promising treatment option in hematological cancers, including B-cell lymphomas. Four CAR T-cell therapies targeting CD19 are currently approved for B-cell lymphomas: axicabtagene ciloleucel (axi-cel) is approved for diffuse large B-cell lymphoma (DLBCL) in the third-line setting, tisagenlecleucel (tisa-cel) is approved for relapsed and refractory DLBCL, lisocabtagene maraleucel (liso-cel) is approved for DLBCL, and brexucabtagene autoleucel (brexu-cel) is approved for relapsed or refractory MCL.

While research on CAR T-cell therapy is limited in MCL compared with other types of cancer, the review authors highlight 2 trials of brexu-cel and liso-cel in relapsed and refractory MCL.

In the phase 2 ZUMA-2 trial (NCT02601313) of brexu-cel, the first multicenter trial of CAR T-cell therapy in relapsed and refractory MCL, patients who had received 2 or more lines of therapy prior to brexu-cel were given a single infusion. It was highly active in the cohort used for efficacy analysis, with a 93% overall response rate (ORR) and 67% of patients achieving complete response (CR). In the overall cohort of 74 patients, the ORR was 85%, and 59% of patients achieved CR. At 17.5 months of follow-up, 48% of patients remained in response. Hematological toxicity was the most common adverse event (AE), with 94% of patients experiencing grade 3 or higher toxicity.

The TRANSCEND NHL 001 study (NCT02631044) of liso-cell included multiple types of lymphoma. In 32 patients who were infused with liso-cel, the ORR was 84%, and 59% of patients achieved CR. The most common grade 3 or greater AEs were hematologic toxicities, which affected 34% of patients.

In the future, different combinations and novel agents such as second-generation BTK inhibitors that are currently in development may produce more favorable results for patients with MCL. Determining proper sequencing for combination therapies and the best ways to use CAR T-cell therapy are also important factors, the authors noted.

While there has been progress in MCL research and treatment development, it still remains incurable, and the authors point to novel targeted agents and potential combinations with CAR T-cell therapies as likely future routes for progress.

Reference

Tbakhi B, Reagan PM. Chimeric antigen receptor (CAR) T-cell treatment for mantle cell lymphoma (MCL).Ther Adv Hematol. Published online February 26, 2022. doi:10.1177/20406207221080738

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Current Strategies and the Potential of CAR T-Cell Therapy in Relapsed and Refractory MCL - AJMC.com Managed Markets Network

Every dollar raised for the St. Jude Dream Home Giveaway will help towards finding a cure for childhood cancer by funding the research to save lives.

One of those little lives is a 12-year-old girl who lives here in Virginia. In a single sentence, Leah Duggan explained how her treatment at St. Jude was, for her, the difference between life and death: "I wouldn't be here."

Leah was diagnosed with a rare and very aggressive form of leukemia when she was just a baby. Her cancer did not respond to standard chemotherapy treatments, so the family turned to St. Jude. That's where Leah was able to undergo a stem cell transplant using her mom's cells.

Today, Leah is a healthy, active middle schooler who plays soccer. Her mom Kate credits St. Jude for saving her daughter's life, and how grateful they are to celebrate 11 years in remission.

"Her cancer was just so aggressive and she was kind of out of options, so with really nowhere else to turn, thankfully St. Jude exists and they knew what to do," Kate Duggan said. "They said, 'Hey, we know how to treat your child, we have a clinical trial and it would be perfect for her, bring her on down.' So we packed up and moved to Memphis and stayed there. The rest is history."

That's what St. Jude provides: hope.

You can reserve your ticket for the St. Jude Dream Home Giveaway by clicking here or picking one up at any Southern Bank location. As an added bonus, if you buy your ticket by Friday, March 25, you'll be eligible to win a $10,000 gift card.

The prizes are nice, but every dollar will go towards life-saving treatment for children in need.

Read more from the original source:
'I wouldn't be here': Virginia girl, celebrating 11 years in remission, credits St. Jude with saving her life - News 3 WTKR Norfolk

Researchers are harnessing the tools of genetic engineering to develop potential treatments for human hair loss. dNovo, a biotech startup, claims to have reprogrammed human stem cells into follicle-forming cells and transferred them into the mouse above which you can see has grown a nice tuft, albeit in an odd location. From Technology Review:

In addition to dNovo, a company called Stemson (its name is a portmanteau of "stem cell" and "Samson") has raised $22.5 million from funders including from the drug company AbbVie. Cofounder and CEO Geoff Hamilton says his company is transplanting reprogrammed cells onto the skin of mice and pigs to test the technology[]

So is stem-cell technology going to cure baldness or become the next false hope? Hamilton, who was invited to give the keynote at this year'sGlobal Hair Loss Summit, says he tried to emphasize that the company still has plenty of research ahead of it. "We have seen so many [people] come in and say they have a solution. That has happened a lot in hair, and so I have to address that," he says. "We're trying to project to the world that we are real scientists and that it's risky to the point I can't guarantee it's going to work."

image: dNovo

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This weird mouse with a tuft of human hair could be the future of a stem cell treatment for baldness - Boing Boing

Four years ago, a small Philadelphia biotech company won U.S. approval for the first gene therapy to treat an inherited disease, a landmark after decades of research aimed at finding ways to correct errors in DNA.

Since then, most of the world's largest pharmaceutical companies have invested in gene therapy, as well as cell therapies that rely on genetic modification. Dozens of new biotech companies have launched, while scientists have taken forward breakthroughs in gene editing science to open up new treatment possibilities.

But the confidence brought on by such advances has also been tempered by safety setbacks and clinical trial results that fell short of expectations. In 2022, the outlook for the field remains bright, but companies face critical questions that could shape whether, and how soon, new genetic medicines reach patients. Here are five:

Food and Drug Administration approval of Spark Therapeutics' blindness treatment Luxturna a first in the U.S. came in 2017. A year and a half later, Novartis' spinal muscular atrophy therapy Zolgensma won a landmark OK.

But none have reached market since, with treatments from BioMarin Pharmaceutical and Bluebird bio unexpectedly derailed or delayed.

That could change in 2022. Two of Bluebird's treatments, for the blood disease beta thalassemia and a rare brain disorder, are now under review by the FDA, with target decision dates in May and June. BioMarin, after obtaining more data for its hemophilia A gene therapy, plans to soon approach the FDA about resubmitting an application for approval.

Others, such as CSL Behring and PTC Therapeutics, are also currently planning to file their experimental gene therapies with the FDA in 2022.

Approvals, should they come, could provide important validation for their makers and expand the number of patients for whom genetic medicines are an option. In biotech, though, approvals aren't the end of the road, but rather the mark of a sometimes challenging transition from research to commercial operations. With price tags expected to be high, and still outstanding questions around safety and long-term benefit, new gene therapies may prove difficult to sell.

A record $20 billion flowed into gene and cell therapy developers in 2020, significantly eclipsing the previous high-water mark set in 2018.

Last year, the bar was set higher still, with a total of $23 billion invested in the sector, according to figures compiled by the Alliance for Regenerative Medicine. About half of that funding went toward gene therapy developers specifically, with a similar share going to cell-based immunotherapy makers.

Driving the jump was a sharp increase in the amount of venture funding, which rose 73% to total nearly $10 billion, per ARM. Initial public offerings also helped, with sixteen new startups raising at least $50 million on U.S. markets.

Entering 2022, the question facing the field is whether those record numbers will continue. Biotech as a whole slumped into the end of last year, with shares of many companies falling amid a broader investment pullback. Gene therapy developers, a number of which had notable safety concerns crop up over 2021, were hit particularly hard.

Moreover, many startups that jumped to public markets hadn't yet begun clinical trials roughly half of the 29 gene and cell therapy companies that IPO'd over the past two years were preclinical, according to data compiled by BioPharma Dive. That can set high expectations companies will be hard pressed to meet.

Generation Bio, for example, raised $200 million in June 2020 with a pipeline of preclinical gene therapies for rare diseases of the liver and eye. Unexpected findings in animal studies, however, sank company shares by nearly 60% last December.

Still, the pace of progress in gene and cell therapy is fast. The potential is vast, too, which could continue to support high levels of investment.

"I think fundamentally, investment in this sector is driven by scientific advances, and clinical events and milestones," said Janet Lambert, ARM's CEO, in an interview. "And I think we see those in 2022."

The potential of replacing or editing faulty genes has been clear for decades. How to do so safely has been much less certain, and concerns on that front have set back the field several times.

"Safety, safety and safety are the first three top-of-mind risks," said Luca Issi, an analyst at RBC Capital Markets, in an interview.

Researchers have spent years making the technology that underpins gene therapy safer and now have a much better understanding of the tools at their disposal. But as dozens of companies push into clinical trials, a number of them have run into safety problems that raise crucial questions for investigators.

In trials run by Audentes Therapeutics and by Pfizer (in separate diseases), study volunteers have tragically died for reasons that aren't fully understood. UniQure, Bluebird bio and, most recently, Allogene Therapeutics have reported cases of cancer or worrisome genetic abnormalities that triggered study halts and investigations.

While the treatments being tested were later cleared in the three latter cases, the FDA was sufficiently alarmed to convene a panel of outside experts to review potential safety risks last fall. (Bluebird recently disclosed a new hold in a study of its sickle cell gene therapy due to a patient developing chronic anemia.)

The meeting was welcomed by some in the industry, who hope to work with the FDA to better detail known risks and how to avoid them in testing.

"[There's] nothing better than getting people together and talking about your struggles, and having FDA participate in that," said Ken Mills, CEO of gene therapy developer Regenxbio, in an interview. "The biggest benefit probably is for the new and emerging teams and people and companies that are coming into this space."

Safety scares and setbacks are likely to happen again, as more companies launch additional clinical trials. The FDA, as the recent meeting and clinical holds have shown, appears to be carefully weighing the potential risks to patients.

But, notably, there hasn't been a pullback from pursuing further research, as has happened in the past. Different technologies and diseases present different risks, which regulators, companies and the patient community are recognizing.

"We're by definition pushing the scientific envelope, and patients that we seek to treat often have few or no other treatment options," said ARM's Lambert.

Last June, Intellia Therapeutics disclosed early results from a study that offered the first clinical evidence CRISPR gene editing could be done safely and effectively inside the body.

The data were a major milestone for a technology that's dramatically expanded the possibility for editing DNA to treat disease. But the first glimpse left many important questions unanswered, not least of which are how long the reported effects might last and whether they'll drive the kind of dramatic clinical benefit gene editing promises.

Intellia is set to give an update on the study this quarter, which will start to give a better sense of how patients are faring. Later in the year the company is expecting to have preliminary data from an early study of another "in vivo" gene editing treatment.

In vivo gene editing is seen as a simpler approach that could work in more diseases than treatments that rely on stem cells extracted from each patient. But it's also potentially riskier, with the editing of DNA taking place inside the body rather than in a laboratory.

Areas like the eye, which is protected from some of the body's immune responses, have been a common first in vivo target by companies like Editas Medicine. But Intellia and others are targeting other tissues like the liver, muscle and lungs.

Later this year, Verve Therapeutics, a company that uses a more precise form of gene editing called base editing, plans to treat the first patient with an in vivo treatment for heart disease (which targets a gene expressed in the liver.)

"The future of gene editing is in vivo," said RBC's Issi. His view seems to be shared by Pfizer, which on Monday announced a $300 million research deal with Beam Therapeutics to pursue in vivo gene editing targets in the liver, muscle and central nervous system.

With more and more cell and gene therapy companies launching, the pipeline of would-be therapies has grown rapidly, as has the number of clinical trials being launched.

Yet, many companies are exploring similar approaches for the same diseases, resulting in drug pipelines that mirror each other. A September 2021 report from investment bank Piper Sandler found 21 gene therapy programs aimed at hemophilia A, 19 targeting Duchenne muscular dystrophy and 18 going after sickle cell disease.

In gene editing, Intellia, Editas, Beam and CRISPR Therapeutics are all developing treatments for sickle cell disease, with CRISPR the furthest along.

As programs advance and begin to deliver more clinical data, companies may be forced into making hard choices.

"[W]e think investors will place greater scrutiny as programs enter the clinic and certain rare diseases are disproportionately pursued," analysts at Stifel wrote in a recent note to investors, citing Fabry disease and hemophilia in particular.

This January, for example, Cambridge, Massachusetts-based Avrobio stopped work on a treatment for Fabry that was, until that point, the company's lead candidate. The decision was triggered by unexpected findings that looked different than earlier study results, but Avrobio also cited "multiple challenging regulatory and market dynamics."

Read more here:
5 questions facing gene therapy in 2022 - BioPharma Dive

What are stem cells?

All of the blood cells in your body - white blood cells, red blood cells, and platelets - start out as young (immature) cells called hematopoietic stem cells. Hematopoietic means blood-forming.These are very young cells that are not fully developed. Even though they start out the same, these stem cells can mature into any type of blood cell, depending on what the body needs when each stem cell is developing.

Stem cells mostly live in the bone marrow (the spongy center of certain bones). This is where they divide to make new blood cells. Once blood cells mature, they leave the bone marrow and enter the bloodstream. A small number of the immature stem cells also get into the bloodstream. These are called peripheral blood stem cells.

Stem cells make red blood cells, white blood cells, and platelets. We need all of these types of blood cells to keep us alive. For these blood cells to do their jobs, you need to have enough of each of them in your blood.

Red blood cells carry oxygen away from the lungs to all of the cells in the body. They bring carbon dioxide from the cells back to the lungs to be exhaled. A blood test called a hematocrit shows how much of your blood is made up of RBCs. The normal range is about 35% to 50% for adults. People whose hematocrit is below this level have anemia. This can make them look pale and feel weak, tired, and short of breath.

White blood cells help fight infections caused by bacteria, viruses, and fungi. There are different types of WBCs.

Neutrophilsare the most important type in fighting infections. They are the first cells to respond to an injury or when germs enter the body. When they are low, you have a higher risk of infection. The absolute neutrophil count (ANC) is a measure of the number of neutrophils in your blood. When your ANC drops below a certain level, you have neutropenia. The lower the ANC, the greater the risk for infection.

Lymphocytesare another type of white blood cell. There are different kinds of lymphocytes, such as T lymphocytes (T cells), B lymphocytes (B cells), and natural killer (NK) cells. Some lymphocytes make antibodies to help fight infections. The body depends on lymphocytes to recognize its own cells and reject cells that dont belong in the body, such as invading germs or cells that are transplanted from someone else.

Platelets are pieces of cells that seal damaged blood vessels and help blood to clot, both of which are important in stopping bleeding. A normal platelet count is usually between 150,000/cubic mm and 450,000/cubic mm, depending on the lab that does the test. A person whose platelet count drops below normal is said to have thrombocytopenia, and may bruise more easily, bleed longer, and have nosebleeds or bleeding gums. Spontaneous bleeding (bleeding with no known injury) can happen if a persons platelet count drops lower than 20,000/mm3. This can be dangerous if bleeding occurs in the brain, or if blood begins to leak into the intestines or stomach.

You can get more information on blood counts and what the numbers mean in Understanding Your Lab Test Results.

Depending on the type of transplant thats being done, there are 3 possible sources of stem cells to use for transplants:

Bone marrow is the spongy liquid tissue in the center of some bones. It has a rich supply of stem cells, and its main job is to make blood cells that circulate in your body. The bones of the pelvis (hip) have the most marrow and contain large numbers of stem cells. For this reason, cells from the pelvic bone are used most often for a bone marrow transplant. Enough marrow must be removed to collect a large number of healthy stem cells.

The bone marrow is harvested (removed) while the donor is under general anesthesia (drugs are used to put the patient into a deep sleep so they dont feel pain). A large needle is put through the skin on the lower back and into the back of the hip bone. The thick liquid marrow is pulled out through the needle. This is repeated until enough marrow has been taken out. (For more on this, see Whats It Like to Donate Stem Cells?)

The harvested marrow is filtered, stored in a special solution in bags, and then frozen. When the marrow is to be used, its thawed and then put into the patients blood through a vein, just like a blood transfusion. The stem cells travel to the bone marrow, where they engraft or take and start to make blood cells. Signs of the new blood cells usually can be measured in the patients blood tests in a few weeks.

Normally, not many stem cells are found in the blood. But giving stem cell donors shots of hormone-like substances called growth factors a few days before the harvest makes their stem cells grow faster and move from the bone marrow into the blood.

For a peripheral blood stem cell transplant, the stem cells are taken from blood. A special thin flexible tube (called a catheter) is put into a large vein in the donor and attached to tubing that carries the blood to a special machine. The machine separates the stem cells from the rest of the blood, which is returned to the donor during the same procedure. This takes several hours, and may need to be repeated for a few days to get enough stem cells. The stem cells are filtered, stored in bags, and frozen until the patient is ready for them. (For more on this, see Whats It Like to Donate Stem Cells?)

When theyre given to the patient, the stem cells are put into a vein, much like a blood transfusion. The stem cells travel to the bone marrow, engraft, and then start making new, normal blood cells. The new cells are usually found in the patients blood in about 4 weeks.

The blood of newborn babies normally has large numbers of stem cells. After birth, the blood thats left behind in the placenta and umbilical cord (known as cord blood) can be taken and stored for later use in a stem cell transplant. Cord blood can be frozen until needed. A cord blood transplant uses blood that normally is thrown out after a baby is born. After the baby is born, specially trained members of the health care team make sure the cord blood is carefully collected. The baby is not harmed in any way. More information on donating cord blood can be found in Whats It Like to Donate Stem Cells?

Even though the blood of newborns has large numbers of stem cells, cord blood is only a small part of that number. So, a possible drawback of cord blood is the smaller number of stem cells in it. But this is partly balanced by the fact that each cord blood stem cell can form more blood cells than a stem cell from adult bone marrow. Still, cord blood transplants can take longer to take hold and start working. Cord blood is given into the patients blood just like a blood transfusion.

Some cancers start in the bone marrow and others can spread to it. Cancer attacks the bone marrow, causing it to make too many of some cells that crowd out others, or causing it to make cells that arent healthy and don't work like they should. For these cancers to stop growing, they need bone marrow cells to work properly and start making new, healthy cells.

Most of the cancers that affect bone marrow function are leukemias, multiple myeloma, and lymphomas. All of these cancers start in blood cells. Other cancers can spread to the bone marrow, which can affect how blood cells function, too.

For certain types of leukemia, lymphoma, and multiple myeloma, a stem cell transplant can be an important part of treatment. The goal of the transplant is to wipe out the cancer cells and the damaged or non-healthy cells that aren't working right, and give the patient new, healthy stem cells to start over."

Stem cell transplants are used to replace bone marrow cells that havebeen destroyed by cancer or destroyed by the chemo and/or radiation used to treat the cancer.

There are different kinds of stem cell transplants. They all use very high doses of chemo (sometimes along with radiation) to kill cancer cells. But the high doses can also kill all the stem cells a person has and can cause the bone marrow to completely stop making blood cells for a period of time. In other words, all of a person's original stem cells are destroyed on purpose. But since our bodies need blood cellsto function, this is where stem cell transplants come in. The transplanted stem cells help to "rescue" the bone marrow by replacingthe bodys stem cells that have been destroyedby treatment. So, transplanting the healthy cellslets doctors use much higher doses of chemo to try to kill all of the cancer cells, and the transplanted stem cells can grow into healthy, mature blood cells that work normally and reproduce cells that are free of cancer.

There's another way astem cell transplant can work, if it's a transplant that uses stem cells from another person (not the cancer patient). In these cases, the transplant can help treat certain types of cancer in a way other than just replacing stem cells. Donated cells can often find and kill cancer cells better than the immune cells of the person who had the cancer ever could. This is called the graft-versus-cancer or graft-versus-leukemia effect. The "graft" is the donated cells. The effect means that certain kinds of transplants actually help kill off the cancer cells, along with rescuing bone marrow and allowing normal blood cells to develop from the stem cells.

Although a stem cell transplant can help some patients, even giving some people a chance for a cure, the decision to have a transplant isnt easy. Like everything in your medical care, you need to be the one who makes the final choice about whether or not youll have a stem cell transplant. Transplant has been used to cure thousands of people with otherwise deadly cancers. Still, there arepossible risks and complications that can threaten life, too. People have died from complications of stem cell transplant. The expected risks and benefits must be weighed carefully before transplant.

Your cancer care team will compare the risks linked with the cancer itself to the risks of the transplant. They may also talk to you about other treatment options or clinical trials. The stage of the cancer, patients age, time from diagnosis to transplant, donor type, and the patients overall health are all part of weighing the pros and cons before making this decision.

Here are some questions you might want to ask. For some of these, you may need to talk to the transplant team or the people who work with insurance and payments for the doctors office and/or the hospital:

Be sure to express all your concerns and get answers you understand. Make sure the team knows whats important to you, too. Transplant is a complicated process. Find out as much as you can and plan ahead before you start.

Its important to know the success rate of the planned transplant based on your diagnosis and stage in treatment, along with any other conditions that might affect you and your transplant. In general, transplants tend to work better if theyre done in early stages of disease or when youre in remission, when your overall health is good. Ask about these factors and how they affect the expected outcomes of your transplant or other treatment.

Many people get a second opinion before they decide to have a stem cell transplant. You may want to talk to your doctor about this, too. Also, call your health insurance company to ask if they will pay for a second opinion before you go. You might also want to talk with them about your possible transplant, and ask which transplant centers are covered by your insurance.

Stem cell transplants cost a lot, and some types cost more than others. For example, getting a donor's cells costs more than collecting your own cells. And, different drug and radiation treatments used to destroy bone marrow can have high costs. Some transplants require more time in the hospital than others, and this can affect cost. Even though there are differences, stem cell transplants can cost hundreds of thousands of dollars.

A transplant (or certain types of transplants) is still considered experimental for some types of cancer, especially some solid tumor cancers, so insurers might not cover the cost.

No matter what illness you have, its important to find out what your insurer will cover before deciding on a transplant, including donor match testing, cell collection, drug treatments, hospital stay, and follow-up care. Go over your transplant plan with them to find out whats covered. Ask if the doctors and transplant team you plan to use are in their network, and how reimbursement will work. Some larger insurance companies have transplant case managers. If not, you might ask to speak with a patient advocate. You can also talk with financial or insurance specialists at your doctors office, transplant center, and hospital about what expenses you are likely to have. This will help you get an idea of what you might have to pay in co-pays and/or co-insurance.

The National Foundation for Transplants (NFT) provides fund raising guidance to help patients, their families, and friends raise money for all types of stem cell transplants in the US. They can be reached online at http://www.transplants.org, or call 1-800-489-3863.

Originally posted here:
How Stem Cell and Bone Marrow Transplants Are Used to ...

At the University of Chicago Medicine, our transplant team works side-by-side with the patient, family and referring physician before, during and after transplantation to ensure the best possible outcome. The transplant process differs from patient to patient, but generally includes:

Most patients undergoing stem cell transplantation are cared for in our dedicated unit for approximately one week before and two to three weeks after the procedure. Select patients may receive outpatient stem cell transplant care in specially designed treatment rooms within the unit. The same physicians and nurses who provide inpatient care provide outpatient care.

The stem cell transplant unit is located on the top floor of the Center for Care and Discovery and features state-of-the-art technology and thoughtful amenities:

Our stem cell transplant physicians are members of the nationally renowned UChicago Medicine Comprehensive Cancer Center,one of only two National Cancer Institute (NCI)-designated Comprehensive Cancer Centers in Chicago. It is through the Cancer Center that we participate in clinical trials of emerging therapies. In addition, we are active participants in the Alliance for Clinical Trials in Oncology and the Blood and Marrow Transplant Clinical Trials Network. Involvement in these vital research organizations gives our patients access to the most novel and exciting treatments available.

Our stem cell transplant program laboratory is specially equipped to handle all of the blood and stem cell preparation necessary for transplant, including apheresis (separation and collection of stem cells from the blood) and cryopreservation (freezing of stem cells for future use).

Leading-edge technologies in the laboratory enable us to perform complex procedures that help improve transplant outcomes. These procedures include purging of cancerous cells and purifying donor stem cells to minimize graft-versus-host disease (a serious side effect related to the use of donor cells for transplant).

Originally posted here:
The Stem Cell Transplant Process - UChicago Medicine

Fans of bodybuilding are familiar with the health struggles that have plagued eight-time Mr. Olympia Ronnie Coleman in recent years. Coleman has endured over a dozen surgeries to his neck and back and, as a result, walks with crutches. Through it all, Coleman maintains a positive spirit and remains optimistic thanks in part to two stem cell treatments, which are starting to pay off.

Coleman joined co-host Giles Thomas in a recent episode of the Aint Nothing but a Podcast show. In the video, released on Dec. 29, 2021, Coleman says that hes beginning to feel like his old self again, and his weight gain reflects his health improvements.

Sporting a Ronnie Coleman Signature Series shirt that showed off his noticeable arm improvement, the Texas native his home revealed that hes back up to 285 pounds. And if youre having trouble believing that Coleman weighs close to what he did in his competitive prime, youre not alone.

I weighed myself five times on the scale downstairs, and I thought maybe its because Im downstairs,' Coleman said on the podcast episode. I was freaking out, so I went upstairs, and [that scale] was the same. I was like wow.'

BarBend reached out to the 2016 International Sports Hall of Fame inductee directly to follow up on what he revealed on his podcast. Coleman was happy to share more about his progress, including what he considers the best improvement of all the return of his signature leg size.

Thats the thing Im most proud of, Coleman tells BarBend. My legs had atrophied a whole lot since 2016 when I went in and had my first surgery 2017, same thing, 2018, 2019, 2020, same thing. I was just about to give up on it, you know. Then, suddenly, about four months ago, I started feeling a pump in my legs. And then I noticed the size had come back, and the atrophy was gone. I was geeked!

The man considered the most legendary bodybuilder of all time wasnt just known for being big. His freakish feats of strength including an 800-pound back squat and deadlift only added to the mystique he brought to the stage.

While Coleman isnt going to be moving that kind of weight anytime soon, hes been more active on social media, sharing training clips, such as the one below in which he performed a set of leg extensions on Dec. 12, 2021.

Coleman isnt leg-pressing 2,300 pounds as he did in his prime, but he is throwing more 45s on the machine nowadays than during his recovery.

Im back up to doing five plates, one each side, up from three per side a few months ago, Coleman says.

The eight-time Mr. Olympias improvements arent exclusively in the lower body. Coleman shared that hes getting stronger on numerous lifts in the gym. For example, Coleman is moving weight, performing 20 reps of rear lateral raises. The new size is evident, and his trademark smile was on full display during the set (see below).

My strength has come up a whole lot. Im going to say that its up about 40 percent.

He used the flat dumbbell press as another example, saying that he is now working with 70-pound dumbbells for his sets of 20 reps, which he does for every lift. He is training six days a week, as he did during his reign as the number one bodybuilder on the planet.

Returning leg strength is undoubtedly a strong sign that Colemans physical health is improving. That said, the former police officer mentions that itll still be a while before hes able to ditch the crutches.

My feet are still numb, and my quads are still numb, but theyre not quite as numb. I can start to feel them a little bit, he says. Once Im able to relieve this numbness, I will stand a much better chance of balancing myself.

Coleman says that the stem cell specialist told him that nerve regeneration takes about two years. As Coleman explains on the podcast, the specialists claim was verified when the numbness in his neck went away after two years, almost to the day. Coleman is confident that the same will happen with his lower extremities.

I thought about what the doctor said, and he was right. Thats what Im looking at now. It will be about two years before I get my full mobility and balance back. Then I can work on walking unassisted.

With his most recent stem cell treatment having taken place on Dec. 27, 2021, Coleman is optimistic that hell keep on progressing. This positive news caps off a good year overall for the 57-year-old icon.

In September, he was honored with the Arnold Classic Lifetime Achievement award by fellow Mr. Olympia Arnold Schwarzenegger. As great as that honor was, hes even more excited to get back out to events and meet fans now that he is in better shape and spirits I cant wait!

Featured Image: @ronniecoleman8 on Instagram

Originally posted here:
Exclusive: Ronnie Coleman on Recent Weight Gain, Current Strength, and Health Progress - BarBend