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Breakthrough Therapies in Cancer: CAR T-Cell Therapies

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With each passing day, we inch closer to curing cancer.

Until now, the cancer treatment universe was limited to 4 modalities, namely Surgery, Radiation, Chemotherapy and Targeted Drug Treatments. Recently, we have witnessed the addition of a fifth front in the battle against cancer, called Immunotherapy.

In Immunotherapy, scientists have been trying to develop ways to train the human immune system to fight and kill cancer-cells, just like they kill germs in trivial disorders such as the common cold. This technique of harnessing the immune system, is called “Adaptive Cell Transfer” or ACT.

CAR T-Cell Therapies have emerged as the most promising form of Immunotherapy.

What are CAR T-cell Therapies?

When we get sick with the common cold, our immune system attacks the infectious germs and kills them, effectively curing us. What is at work here are a type of cells present in our blood called T-cells. T-cells have the unique ability to identify affected cells, latch on to them and kill them.For a long time, cancer researchers have wondered if it’s possible to train our immune system to kill cancer cells the same way, and effectively become cancer-free. This field of study, titled ‘Immunotherapy’ has been widely researched, and Chimeric Antigen Receptor (CAR) T-Cell Therapies are one of the most exciting advancements in this field.

In a CAR T-cell therapy, a patient’s T-cells are genetically engineered, so that they attach themselves to cancer cells and kill them. More specifically, such T-cells are extracted from the patient’s own blood. These cells are then engineered in a lab to identify specific proteins (or antigens) present within cancer cells, and then these cells are injected back into the patient’s bloodstream.

Many scientists refer to CAR T-Cell Therapies as ‘Living Drugs’ because they constantly attach cancer cells, thereby reducing the rates of recurrence/relapse significantly.

The National Cancer Institute recently issued a simple graphical representation of such therapies on their Twitter feed:
Additionally, the Dana-Farber Cancer Institute has published a video explaining how CAR T-Cell Therapies work:

Current Status of Car T-Cell Therapies

The use of Car T-cell therapies has been limited to clinical trials so far. In these trials, many patients in advanced stages of cancer have experienced positive effects. Many such trials involved patients suffering from advanced ALL (Acute Lymphoblastic Leukemia) with limited treatment options. Most patients experienced 100% remission, and many of them remained in remission for prolonged periods of time.Similar promising results have been observed in the case of lymphoma patients. For patients with ALL, the first line of treatment is usually chemotherapy, followed by a bone marrow transplant. But if the cancer relapses, the treatment options get increasingly thin, close to none. CAR T-cell Therapies act as breakthrough treatments in such cases. So far, the clinical trials have shown positive results. In a trial conducted at the Children’s hospital of Philadelphia (CHOP), 27 out of 30 patients, showed all signs of cancer disappear completely.

Latest Developments

  • The United States FDA has recently approved CAR T-cell therapies for a subtype of ‘B’ cell Acute Leukemias in children (Kymriah) and another one for refractory ‘B’ cell Lymphomas in adults (Yescarta).
  • In another trial conducted on ALL patients at the Memorial Sloan Kettering Cancer center, 14 out of 16 patients demonstrated total recovery, some of them as early as 2 weeks into the treatment.

Potential Side Effects, Toxicity and Management

While the side-effects of such treatments can be life-threatening, the medical fraternity has developed sustainable safeguards against such effects, with supportive treatments. Some of these side effects are listed below:

  1. Cytokine Release Syndrome (CRS) – CRS may cause high fevers, low blood pressure or poor lung oxygenation. Some patients experience delirium, confusion and seizure while undergoing treatment. Such symptoms typically appear within the first week of treatment, and are usually reversible.
  2. Tumour Lysis Syndrome (TLS) – TLS includes a group of metabolic complications that can occur due to the breakdown of dying cells, usually at the onset of toxic cancer treatments. However, TLS can occur a month or more after CAR T-cell therapy. TLS can be a life-threatening complication arising from any treatment that causes cancer cells to break down, including CAR T-cells. This complication has been managed by standard supportive therapy.
  3. B-cell Aplasia – Since T-cells are targeted against surface receptors of B-cells, the normal B-cells also get dystroyed by them. However, no significant or long term side effects have been recorded.

In addition to these side effects, ScienceDirect.com has published a summary of various clinical trials conducted in the field, highlighting their effectiveness in hematologic disorders as compared to results in cases of solid tumors.

For solid tumours, there are a few challenges such as higher risk of major complications and a difficult tumour microenvironment for these cells to be effective. But these hurdles are surmountable, and we will eventually witness better results with this revolutionary approach.
-Dr Amit Jotwani (Co-founder, Onco.com and Senior Consultant Oncologist)

What’s Next in CAR T-cell Therapies?

CAR T-cell therapies seem to have a lot of potential, but further research is needed to make them mainstream and available to patients globally. Many labs around the world are currently testing these therapies, not just for blood cancer but also for solid tumors such as pancreatic and brain cancers. Given the amount of interest the field has generated among researchers worldwide, it is likely that the next decade will be transformative in defining the cancer treatment paradigm.

Watch the video. URL:https://youtu.be/OadAW99s4Ik

References:

1. LLS.org – Article on Chimeric Antigen Receptor T-Cell Therapies
2. ESMO.org – The Evolving Field Of CAR T-Cell Therapies
3. Nature.com – CAR T-Cell Therapies Journal
4. Cancer.gov – The National Cancer Institute’s take on CAR T-Cell Therapies
4. ScienceDirect.com – Toxicity & Management in CAR T-Cell Therapy

Maternal Retinoids Increase PDGFRα+ Progenitor Population and Beige Adipogenesis in Progeny by Stimulating Vascular Development.

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Highlights

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Maternal vitamin A supplementation increases blood vessel density and expands adipose progenitor population in progeny.

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Maternal vitamin A supplementation enhances brown-like phenotype in adipose tissues.

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Maternal vitamin A supplementation protects offspring from diet induced obesity.

Vitamin A and its metabolite, retinoic acid, play key roles in adipogenesis and energy expenditure of adipose tissues. In mice and humans, vitamin A intake is inversely correlated with adiposity. This study has uncovered a role for maternal retinoids in fetal adipose development. Maternal vitamin A supplementation or RA administration increases adipose progenitor population and promotes beige adipogenesis, which protects offspring from diet induced obesity in later life.

Abstract

Maternal vitamin A intake varies but its impact on offspring metabolic health is unknown. Here we found that maternal vitamin A or retinoic acid (RA) administration expanded PDGFRα+ adipose progenitor population in progeny, accompanied by increased blood vessel density and enhanced brown-like (beige) phenotype in adipose tissue, protecting offspring from obesity. Blockage of retinoic acid signaling by either BMS493 or negative RA receptor (RARαDN) over-expression abolished the increase in blood vessel density, adipose progenitor population, and beige adipogenesis stimulated by RA. Furthermore, RA-induced beige adipogenesis was blocked following vascular endothelial growth factor receptor (VEGFR) 2 knock out in PDGFRα+ cells, suggesting its mediatory role. Our data reveal an intrinsic link between maternal retinoid level and offspring health viapromoting beige adipogenesis. Thus, enhancing maternal retinoids is an amiable therapeutic strategy to prevent obesity in offspring, especially for those born to obese mothers which account for one third of all pregnancies.

Discussion

In this study, we found that maternal retinoid supplementation profoundly enhances brown/beige adipogenesis during fetal development, which has long-term effect on BAT and beige phenotype in offspring, and protects offspring from diet-induced obesity. This is an exciting discovery considering the easiness of vitamin A supplementation and the wide existence of vitamin A deficiency worldwide (WHO, 2009), particularly in low income countries. Low income correlates with obesity and metabolic diseases (Pan et al., 2013).

We identified that maternal retinoid status affects fetal and offspring brown/beige adipogenesis through promoting angiogenesis. Maternal vitamin A or RA supplementation enhances angiogenesis through upregulating Vegfa and Vegfr2expression, which consequently increased the population of PDGFRα+ adipose progenitor cells in adipose tissue. Our data are consistent the enhanced angiogenesis in both white and brown adipose tissues of mice exposed to cold stimulus, where Vegfr2blockage abolishes the cold-induced angiogenesis and impairs nonshivering thermogenesis capacity ( Xue et al., 2009). Although it remains controversial whether beige adipocytes are generated by de novo adipogenesis or conversion of existing adipocytes ( Rosenwald et al., 2013 ;  Wang et al., 2013), progenitor cells on endothelial vessels are capable to differentiate into beige adipocytes ( Tran et al., 2012; Min et al., 2016 ;  Vishvanath et al., 2016). Obesity and diabetes impair the angiogenic potential of adipose tissue stem cells ( Rennert et al., 2014 ;  Togliatto et al., 2016), and stimulation of angiogenesis via Vegfa over-expression promotes adipose tissue thermogenesis and protects against diet-induced obesity ( Wu et al., 2011 ;  Sun et al., 2014a). Thus, enhancing angiogenesis is an effective strategy to promote beige adipogenesis in adipose tissue impaired due to obesity and diabetes.

Besides stimulating angiogenesis, our data also show that maternal vitamin A or RA supplementation up-regulates brown/beige adipogenesis of progenitor cells, which is associated with enhanced expression of Prdm16 and other brown adipocyte genes. Using mice with conditional Vegfr2 knockout specifically in PDGFRα+ progenitor cells, the promotion effect of RA on brown adipogenesis was severely reduced, demonstrating an angiogenesis independent effect of RA on beige adipogenesis. These observations are consistent with previous studies showing that the RA increases oxidation and energy consumption of white adipose tissue in mature animals ( Alvarez et al., 1995; Puigserver et al., 1996; Bonet et al., 2003 ;  Mercader et al., 2006). Thus, maternal RA stimulates both angiogenesis and beige adipogenesis during early development, which are mediated by RAR because its functional knockout blocks brown/beige adipogenesis.

Besides beige adipogenesis, increasing the progenitor pool in adipose tissues through angiogenesis has another advantage. It is known that PDGFRα+ progenitor cells are the source of both beige and white adipocytes (Lee et al., 2012; Lee et al., 2013 ;  Lee et al., 2015). Thus, enhancing PDGFRα+ progenitor cell pool will not only increase beige but also white adipogenesis, as shown by the increased expression of white preadipose genes in MVA WAT of this study. Adipose tissue is the organ to store fat, and an insufficient number of adipocytes leads to adipocyte hypertrophy, hypoxia and inflammation, a key cause of metabolic dysfunction (Rosen and Spiegelman, 2014). Thus, adipocyte hyperplasia has protective effects on metabolic dysfunction induced by excessive energy intake. Consistently, there is one subgroup of people who are metabolically health despite being obese, while others exhibit severe metabolic syndromes (Denis and Obin, 2013). People who are called “metabolically healthy obese” (MHO) tend to have smaller adipocytes (Kloting et al., 2010) and higher mitochondrial transcription (Naukkarinen et al., 2014). These individuals have reduced visceral adiposity, reduced inflammation, improved glucose and lipid homeostasis when compared to other equally obese unhealthy subjects (Denis and Obin, 2013). Based on our discovery, maternal vitamin A or RA supplementation increases the progenitor pool in offspring, which reduces average adipocyte sizes and increases adipocyte hyperplasia, improving overall metabolic health of offspring.

In conclusion, offspring adipose tissue health is substantially improved due to maternal vitamin A or RA supplementation. Maternal vitamin A promotes vascular system development, which consequently increases the population of PDGFRα+ adipose progenitor cells. In addition, maternal vitamin A supplementation strongly upregulates beige adipogenesis of PDGFRα+ progenitor cells. In combination, maternal vitamin A treated offspring have increased beige adipogenesis and smaller adipocyte sizes, which protect offspring against diet-induced obesity and metabolic dysfunction.

Source:sciencedirect.com

Sexually Dimorphic Changes of Hypocretin (Orexin) in Depression.

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Highlights

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Hypocretin (orexin) changes were studied in human postmortem brain in depression.

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A clear sex-related change was found in the hypothalamic hypocretin-1-immunoreactivity in depression.

A rat depression model did not reflect the changes in the hypocretin system in the human brain in depression.

The stress systems of depressed patients are put into a higher gear by genetic and developmental factors. Over-reaction of these systems to stressful environmental situations makes people vulnerable to depression and suicide. This is the first postmortem study on changes in a relatively novel stress system in depression, consisting of the hypothalamic hypocretin neurons and hypocretin receptors in the prefrontal cortex. A clear sex-related change was found in the hypothalamic hypocretin-1-immunoreactivity in depression. Evaluation of the hypocretin system in a frequently used depression animal model, i.e. chronic unpredictable mild stress rats, did not replicate changes found in the hypocretin systems in the human brain in depression.

Abstract

Background

Neurophysiological and behavioral processes regulated by hypocretin (orexin) are severely affected in depression. However, alterations in hypocretin have so far not been studied in the human brain. We explored the hypocretin system changes in the hypothalamus and cortex in depression from male and female subjects.

Methods

We quantified the differences between depression patients and well-matched controls, in terms of hypothalamic hypocretin-1 immunoreactivity (ir) and hypocretin receptors (Hcrtr-receptors)-mRNA in the anterior cingulate cortex (ACC) and dorsolateral prefrontal cortex. In addition, we determined the alterations in the hypocretin system in a frequently used model for depression, the chronic unpredictable mild stress (CUMS) rat.

Results

i) Compared to control subjects, the amount of hypocretin-immunoreactivity (ir) was significantly increased in female but not in male depression patients; ii) hypothalamic hypocretin-ir showed a clear diurnal fluctuation, which was absent in depression; iii) male depressive patients who had committed suicide showed significantly increased ACC Hcrt-receptor-2-mRNA expression compared to male controls; and iv) female but not male CUMS rats showed a highly significant positive correlation between the mRNA levels of corticotropin-releasing hormone and prepro-hypocretin in the hypothalamus, and a significantly increased Hcrt-receptor-1-mRNA expression in the frontal cortex compared to female control rats.

Conclusions

The clear sex-related change found in the hypothalamic hypocretin-1-ir in depression should be taken into account in the development of hypocretin-targeted therapeutic strategies.

Discussion

Our study shows, for the first time in postmortem human brain, that hypothalamic hypocretin/orexin is increased in female – but not in male – depressive patients. In addition, there was a diurnal fluctuation in hypothalamic hypocretin-1-ir in the control subjects, which was absent in depression. Moreover, we observed that Hcrt-receptor-mRNA expression showed differences in the ACC and DLPFC depending on age. Male depressive patients who had committed suicide had significantly increased ACC Hcrt-receptor-2-mRNA expression. Our data thus indicate sex-, brain area-, age-, and potentially suicide-related changes in the hypocretin/orexin system in depression. Finally, a significant positive correlation between hypothalamic CRH-mRNA and prepro-hypocretin-mRNA and a significant increase in Hcrt-receptor-1-mRNA expression in the frontal cortex in female – but not male – CUMS rats strengthen the presence of sexually dimorphic hypocretin/orexin system changes in mood disorder.

4.1. Hypocretin-ir in the Hypothalamus in Depression

It should be noted that the increased IOD of hypocretin-ir may indicate an increase in either hypocretin-expressing neuron number (related to the area stained) and/or staining intensity (measured as OD). An increase of either of these parameters indicates an increased expression of hypocretin protein levels. The significantly increased hypocretin-ir in female depressive patients indicates that hypocretin may play a key role in the etiology of depression, which is more prevalent in females than in males (Piccinelli and Wilkinson, 2000). As we have indicated in the Introduction section, studies have found that Hcrt-receptor-1 gene, or a linked locus, may modulate the risk for mood disorders (Rainero et al., 2011) and Hcrt-receptor-1 gene knockout mice showed increased anxiety-like behavior and altered depression-like behaviors (Abbas et al., 2015). One may thus speculate that the higher levels of hypocretin-1-ir in female patients may enhance depressive symptoms. It should be noted that since all the female subjects studied in our study were in their postmenopausal stage, one would not expect to see the hot flash-related hypocretin changes reported earlier (Federici et al., 2016).

The sex difference in the alterations of hypocretin, which happens in the framework of the stress-hypothesis, was further supported by our animal study, showing a significant positive correlation between hypothalamic prepro-hypocretin-mRNA and CRH-mRNA only in female CUMS rats. In view of this, it is of interest to note that the dual Hcrt-receptor antagonist almorexant was found to prevent HPA axis dysregulation caused by CUMS and offers evidence for the possibility that pharmacological blockade of the hypocretin system induces a robust antidepressant-like effect as well as the restoration of the stress-related HPA axis defect (Nollet et al., 2012). It should be noted, however, that other animal models of depression showed different results in terms of changes in the hypocretin system, such as the genetically depressed Wistar-Kyoto male rats, which showed a lower number and size of hypocretin-1 neurons than its control Wistar male rats (Allard et al., 2004). In another genetically depressed rat model, i.e. the Flinders Sensitive Line (FSL), the number of hypothalamic hypocretin-positive neurons was higher in female FSL rats than in the female control rats, i.e. Flinders Resistant Line (FRL) although this publication by Mikrouli et al. offers no data on male rats (Mikrouli et al., 2011). It is a frequent phenomenon that animal models tend to mimic “just a few symptoms rather than a complete psychiatric disorder”. This is a reason to validate the data obtained in animal models on human postmortem material.

We found a clear day-night fluctuation in hypothalamic hypocretin-1-ir in the control subjects, with higher levels at night, which is similar to the pattern reported for lumbar puncture CSF hypocretin-1 levels obtained by continuous in vivo sampling (Salomon et al., 2003). These findings are in agreement with the concept that hypocretin neurons may play a key role in sleep-wake regulation (Saper, 2013), and the absence of the day-night hypocretin-1-ir fluctuation in depression may thus relate to the frequently occurring symptoms of sleep disorders in this condition. It should be noted that in our earlier research we demonstrated a clear diurnal rhythm in the biological clock, the suprachiasmatic nucleus (SCN), for its main neuropeptide, vasopressin, both on the protein level (Hofman et al., 1993) and on the mRNA level (Zhou et al., 2001) in postmortem material, when the patients were grouped according to time of death. Interestingly, a direct projection from the SCN onto the hypocretin neurons was observed in the brains of rat and human (Abrahamson et al., 2001), which indicates that the SCN may directly regulate the function of hypocretin-immunoreactive neurons. Our finding of the absence of a diurnal hypocretin rhythm in depression agrees with our earlier observation of a diminished SCN function in depression (Zhou et al., 2001). Our data (Zhou et al., 2001) and those of others (Li et al., 2013) thus also show that postmortem studies can indeed reflect the day-night fluctuations during life.

It is of interest to note that in rats the maximal activity of the hypocretin system takes place in their active period, i.e. at night (Mileykovskiy et al., 2005 ;Yoshida et al., 2001) Surprisingly, we found the highest hypocretin-1-ir levels in the human hypothalamus at night. However, this observation agrees with two human studies that reported the lowest CSF hypocretin levels during the daytime (Salomon et al., 2003 ;Grady et al., 2006). This means that the nocturnal elevation of hypocretin-1-ir in the hypothalamus is not simply due to a lack of transport or secretion. A similar phenomenon was observed for melatonin, which is also involved in sleep-wake control: in rats, melatonin levels increase during the dark period (their active phase) and decrease during the light period (rest phase) (Gutjahr et al., 2004), while in humans its levels increase during the dark period (rest phase) and decrease during the light period (active phase) (Zeitzer et al., 2007). The possibility that the diurnal regulation systems act in a different way in a diurnal and a nocturnal species (such as rodents) warrants further investigation.

A recent study showed an age-related decline in the number of hypothalamic hypocretin neurons in the range from 0 to 60 years of age in control subjects (Hunt et al., 2015). We did not find such a correlation, but it should be noted that, unlike in the study by others, the control subjects we studied did not contain very young ages.

4.2. PFC Hcrt-receptors in Depression and in Relation to Suicide

Earlier, our group found, with NBB cortex samples (depression patients without suicide), that the ACC seems to be more vulnerable than the DLPFC to alterations in depression-related molecules, such as nitric oxide synthase, gamma-aminobutyric acid and glutamate (Gao et al., 2013 ;Zhao et al., 2012). In our study, with NBB cortex samples, again we observed a trend for lower Hcrt-receptor-1-mRNA expression in the ACC in depression but no changes in Hcrt-receptors in the DLPFC. The novel finding with SMRI cortex samples (containing depressive patients who committed suicide or died of causes other than suicide) that there was a significantly increased Hcrt-receptor-2-mRNA expression in the ACC, but not in the DLPFC, in male MDD patients who had committed suicide is in agreement with previous findings that the ACC is more vulnerable to suicide than the DLPFC (Zhao et al., 2012 ;  Drevets et al., 2008) and that there is a sex difference in the prevalence of suicide (Maguen et al., 2015). Our data concerning increased ACC Hcrt-receptor-2-mRNA expression in male suicide patients are thus interesting, although too limited for a final conclusion. They do represent, however, a strong rationale for further studies on this topic. Finally, the decreased Hcrt-receptor-1-mRNA expression with aging we observed in the DLPFC may at least partly explain the findings that in SMRI cortex samples (younger) both Hcrt-receptors were detectable in ACC and DLPFC, while in the NBB series (older) Hcrt-receptor-1-mRNA expression was only detectable in ACC and Hcrt-receptor-2-mRNA expression was only detectable in the DLPFC.

Some concerns of the present postmortem brain material study should be mentioned. We did not find significant differences in the hypothalamic hypocretin-1-ir expression between MDD and BD patients, which is in accordance with our previous findings for CRH, AVP and OXT and for receptors in the hypothalamus (Bao et al., 2005 ;  Wang et al., 2008), although a final conclusion on this phenomenon should be based upon a larger sample size. Secondly, one of the inherent potential confounding factors in a postmortem study is medication use. However, we do not think that our main conclusions are cofounded by antidepressants, since increased hypothalamic hypocretin-1-ir was only observed in female depressive patients and increased expression of Hcrt-receptor-2-mRNA in the ACC was only observed in male depressive suicides, although all the depressive groups had been on antidepressants. In addition, animal studies showed that benzodiazepines (Panhelainen and Korpi, 2012), haloperidol (Dalal et al., 2003) and fluoxetine (Nollet et al., 2011), taken by the depressive patients in the present study, may inhibit hypocretin neurons and/or decrease hypocretin levels. Therefore, had antidepressants interfered with our measurements, this would have led to an underestimation of the increased hypocretin-1 levels observed in female depressive patients. It is noted that Calegare et al. found that sub-chronic treatment of adult malerats with fluoxetine increased the levels of prepro-hypocretin mRNA in the hypothalamus without affecting the hypocretin-1 CSF levels ( Calegare et al., 2016). In our study, there were 2 out of 10 male depression patients who had taken fluoxetine, while their hypothalamic hypocretin-1-ir levels (IOD: 0.128 and 0.134) were fully within the range of the other male depression patients (IOD range from 0.103 to 0.248, median value 0.166). Finally, it should also be noted that the Hcrt-receptor data are based upon mRNA measurements and have yet to be confirmed on the protein level.

5. Conclusions

A clear sex-related change was found in the hypothalamic hypocretin-1-ir in depression. The CUMS rat depression model did not replicate changes found in the hypocretin systems in the human brain in depression. Since sex-related changes in hypothalamic hypocretin-1-ir expression were observed in depression, this factor should be taken into account in the development of hypocretin-targeted therapeutic strategies.

Source:sciencedirect.com

Work organization and mental health problems in PhD students

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Highlights

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One in two PhD students experiences psychological distress; one in three is at risk of a common psychiatric disorder.

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The prevalence of mental health problems is higher in PhD students than in the highly educated general population, highly educated employees and higher education students.

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Work and organizational context are significant predictors of PhD students’ mental health.

Abstract

Research policy observers are increasingly concerned about the potential impact of current academic working conditions on mental health, particularly in PhD students. The aim of the current study is threefold. First, we assess the prevalence of mental health problems in a representative sample of PhD students in Flanders, Belgium (N = 3659). Second, we compare PhD students to three other samples: (1) highly educated in the general population (N = 769); (2) highly educated employees (N = 592); and (3) higher education students (N = 333). Third, we assess those organizational factors relating to the role of PhD students that predict mental health status. Results based on 12 mental health symptoms (GHQ-12) showed that 32% of PhD students are at risk of having or developing a common psychiatric disorder, especially depression. This estimate was significantly higher than those obtained in the comparison groups. Organizational policies were significantly associated with the prevalence of mental health problems. Especially work-family interface, job demands and job control, the supervisor’s leadership style, team decision-making culture, and perception of a career outside academia are linked to mental health problems.

Source:sciencedirect.com