Welcome to “Inquiries with the Investigator”

“Inquiries with the Investigator” was enacted in December 2016 as a means for PMC principal scientific investigator Raymond Wong to answer questions relevant to present mesothelioma research, immunotherapy research, as well as research work at the PMC  lab.  Any questions about mesothelioma and immunotherapy research topics can be emailed to Christina at christinam@phlbi.org.

                                                                                       Background Information on PMC Investigator Raymond Wong

Inquiries with Mesothelioma Investigator Ray WongThroughout his career, Raymond Wong, Ph.D. has conducted cancer immunotherapy research in both the academic and biotechnology sectors. His past projects focused on synthetic cancer vaccines and Programmed Death-1 immune checkpoint inhibition using nivolumab (Opdivo®), which is now FDA-approved for treating melanoma and lung cancer. Major advances in the clinical development of immune checkpoint inhibitors for cancer therapy have created much interest in identifying potential synergies with other immunotherapies. Dr. Wong’s current research involves engineering mesenchymal stem cells (MSCs) to deliver immunotherapeutic agents deep into the stroma of tumors.   Ray holds two degrees from the University of Southern California including  a Ph.D.  in Molecular Microbiology and Immunology and a B.S. in Biological Sciences.

 

March 2017

                                                                          Inquiries with Investigator Ray Wong: CAR-T cell Therapy

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  • How does Chimeric Antigen Receptor T-Cell therapy (CAR-T Cell therapy) work?

The current generation of CAR T cell therapies being tested in clinical trials involves a complex manufacturing process.  A patient’s immune cells are first removed from their bloodstream through a process called leukapheresis.  Leukapheresis typically takes 2-4 hours, where a patient is connected to a machine that separates immune cells from the blood, and the remaining components are returned to circulation.  The immune cells are shipped to specialized manufacturing facilities where the T cells in the leukapheresis specimens are genetically engineered to insert specific anti-tumor receptors called chimeric antigen receptors (CAR).  The T cells are simultaneously grown to large numbers over 7-10 days, then shipped back to the patient for intravenous infusion by their oncologist.  CAR T cell therapy is currently combined with chemotherapy, which appears necessary to achieve full effectiveness of CAR T cells.

CAR-T Cell Diagram PNG

  • What are some of the limitations of CAR-T Cell therapy? Which cancers have the best response rate so far?

Other than the two week manufacturing time and high financial cost of treatment, the main limitation is that it thus far only works well in blood cancers like certain leukemias and lymphomas.  There does appear to be a high cure rate in certain blood cancers, with some clinical trials reporting well over 50% complete response rates (disappearance of all disease).  However, solid tumors like mesothelioma have been much more difficult to treat with CAR T cells.  The current prevailing hypothesis is that CAR T cells do not efficiently penetrate solid tumors and/or are shut down by immune suppressive factors often present in solid tumors.

 

  • What are your thoughts on the future of CAR-T-Cell therapy?

Patient safety is still the top concern of CAR T cell therapy.  The FDA has halted some clinic trials as recently as 2016 due to patient deaths.  CAR T cells are very powerful, and can causes excessive immune reactivity resulting in a condition called “cytokine release syndrome,” which can be fatal.  The interaction of CAR T cells combined with chemotherapy is still not fully understood.   The FDA may want several more years of extensive clinical trials to further study safety improvements of CAR T cell therapy.

 

Next-generation CAR T cells may not need to be custom manufactured for each patient.  Researchers are now exploring the use of a gene deletion technology called “clustered regularly interspaced short palindromic repeats” (CRISPR) in the laboratory.  CRISPR might be used to convert T cells from healthy donors into universally compatible CAR T cells.  In laboratory studies, CRISPR can be used to delete proteins on the surface of T cells that normally would cause them to be rejected in genetically unrelated recipients.  If successful, this would allow for bulk manufacturing of “off-the-shelf” CAR T cells ready for immediate use, analogous to universally compatible Type O-negative blood.  CRISPR is also being studied to delete other genes in CAR T cells that would make them more resistant to immune suppression.  This might improve their effectiveness in solid cancers.

 

February 2017

Inquires with the Investigator : Using MSC’s in Placenta’s for Mesothelioma Research

placentaWhat is a placenta?

A placenta is a flattened circular organ that develops in a woman’s uterus during pregnancy. The placenta attaches to the uterine wall and develops an umbilical cord which is then used to provide oxygen and nutrients to the growing baby while simultaneously removing waste products from the baby’s blood. The day of delivery the expectant mother delivers her baby and her placenta. Placentas are usually thrown out by hospitals after delivery, some mothers elect to keep it and have it made into a pill or shake and eat it, while others decide to donate the placenta for research.

 

Placenta Donations to The Pacific Mesothelioma Center

Over the last two years The Pacific Mesothelioma Center has received six placenta donations from families. The placentas biological makeup is rich in mesenchymal stem cells which are ideal for advancing the PMC’s research agenda. This past week Lead Research Investigator Raymond Wong received another placenta donation and took the time to share his process harvesting placentas and explaining their intrinsic value to research.

 

What are you getting out of the placenta and how does it help our research?

Placenta contains mesenchymal stem cells (MSCs), a type of cell that normally serves as a reservoir to replenish tissue – primarily fat, cartilage, and bone.  MSCs can be isolated from placenta and expanded to large numbers for laboratory research and also for medical treatment.  MSCs are of interest to medical researchers as they might be useful for treating certain degenerative conditions such as arthritis, diabetes, heart maladies, and even nervous system injuries.  Due to their natural anti-inflammatory properties, MSCs might also be useful for treating inflammatory conditions such as graft-vs-host disease and Crohn’s disease.  For cancer, MSCs are believed to preferentially migrate to malignant tumors.  This opens the possibility that MSCs can be engineered to deliver anti-cancer drugs preferentially to tumors, thereby increasing the potency of anti-cancer drugs while also limiting toxic side effects.  PHLBI is working on engineering MSCs to deliver immune-boosting proteins as a form of immunotherapy.

 

Explain the significance, if any, of the sex or ethnicity of the baby’s whose placenta is donated?

MSCs harvested and grown from placentas can originate from the mother, the baby, or a mixture of both.  The composition of each batch of MSCs is unpredictable with regard to the exact mixture.  The ethnicity of the mother or baby is unlikely to have significance.  The sex of the baby may influence the level of anti-inflammatory properties of the resulting batch of harvested MSCs.  This might impact the ability of a particular MSC batch to be universally compatible with genetically diverse recipients who are infused with donated MSCs.For reference, the immune system of males vs. females is generally known to be different.  For reference, females have higher incidences of inflammatory disorders, which might suggest that MSCs from a female baby have lower anti-inflammatory properties.  The lower anti-inflammatory properties of female-derived MSCs could possibly make them more prone to being rejected when infused into a genetically unrelated recipient.

newPNG*Pictured above is Lead Investigator Raymond Wong  working on a placenta donation last week in the lab.

 

Describe the process for getting mesenchymal stem cells out of a placenta? How long does it take?      

 Placentas are first cut into small pieces, and then digested for ~2 hours with an enzyme called collagenase to loosen MSCs.  The resulting mixture of digested placental cells contains a very small percentage of MSCs.  By growing the digested placental cell mixture in specialized nutrients, the small number of MSCs is expanded exponentially to large numbers.  This process results in nearly 100% purified MSCs within 3-4 weeks.

 

What is the difference between a placenta from a c-section and placenta from natural birth?

Biologically, there is no difference.  The main impact of c-section vs. natural birth is the amount of microbial contaminants on the placenta when it is obtained.  C-section is a sterile surgery, resulting in lower microbial contaminants.  Natural birth passes the placenta through the virginal canal, resulting in a much larger amount of microbial contaminates (yeast, bacteria, fungus, etc).  Nonetheless, our laboratory protocol for harvesting MSCs utilizes anti-fungal and antibiotic drugs to eliminate microbial contaminants.

 

 How many placenta donations are we looking to have donated each year?                                                              

We have averaged around 2-3 placenta donations each year.

 

 Are any embryonic stem cells cultivated from the placenta?                                                                                                  

MSCs are not embryonic stem cells.  They are considered “adult” stem cells, meaning they are derived from organs that have already developed (bone marrow, placenta, etc).

For questions, additional information, or inquires about how one can donate their placenta to research contact Lead Investigator Raymond Wong at (310)-474-1113 or by email at : rwong@phlbi.org .

 

January 2017

Inquiries with Investigator Raymond Wong : Immunotherapy 

  1. What is immunotherapy and how does it differ from more common types of cancer treatments such as chemotherapy, radiation, and surgery?

Immunotherapy comprises a class of treatments that activate patients’ immune systems to fight cancer.  In general, immunotherapy is better tolerated by patients and has fewer side effects than chemotherapy, radiation, and other molecular-targeted cancer drugs.  Furthermore, unlike chemotherapy, radiation, and surgery, the beneficial effects of immunotherapy often continue even after stopping treatment.  This is due to establishment of immunologic memory, similar to how preventive vaccines can protect an individual for years/decades after initial immunization.

 

  1. Why doesn’t the immune system naturally fight cancer?

Under normal circumstances, the immune system routinely detects and destroys cancer cells (even pre-cancerous cells).   Some cancer cells evade detection by the immune system and progress to form tumors.  This process of immune evasion can be rapid (weeks/months), or prolonged (years/decades).  Multiple mechanisms can allow cancer cells to evade the immune system, such as random mutations in cancer cells, and the overall health of the patient.  Scientists are still trying to fully understand how cancer cells evade the immune system.  Improved understanding of cancer immune evasion will help guide the development of new immunotherapies that effectively reverse these mechanisms.

 

  1. Describe the different types of immunotherapy? Which are the most successful?

Different forms of immunotherapy exist, including vaccines, cytokines, engineered antibodies, and engineered immune cells.  Most immunotherapies are administered intravenously, while some are injected subcutaneously.  The most successfully immunotherapies are immune checkpoint blockers, which are now FDA-approved for multiple cancer types.  Immune checkpoint blockers are engineered antibodies that target specific proteins that impair immune responses against tumors.  The patient’s immune system then becomes more active, sometimes resulting in complete destruction of existing tumors.

Other promising immunotherapies in clinical trials include chimeric antigen receptor (CAR) T cell treatment.  CAR T cells are created by removing T cells from a cancer patient’s circulating blood, engineering them with cancer-targeting receptors, and then re-infusing them back into the patient.  CAR T cells are showing a high cure rate for certain treatment-refractory blood cancers.  However, CAR T cells have limited potency against solid tumors, and side effects can sometimes be severe.  It will likely be years before CAR T cell technology is fully optimized to reduce side effects to acceptable levels.

 

  1. Which cancers are currently FDA-approved for immunotherapy treatment?

Melanoma, prostate cancer, lung cancer, kidney cancer, bladder cancer, and Hodgkin’s lymphoma.  Immunotherapy for other cancer types, like mesothelioma, are typically accessible only through clinical trials.

 

  1. What is the future of immunotherapy? How do you see it changing cancer treatment in the next five years? 

Currently, there is serious discussion of immune checkpoint blocker immunotherapy moving towards first-line treatment for melanoma and lung cancer.  As clinical trials progress, it is possible that these treatments may also become a first-line treatment option for other cancer types.  Combination immunotherapy, whereby different immunotherapy drugs are used together, is now being actively studied in clinical trials.  In fact, the first combination immunotherapy regimen (nivolumab + ipilimumab) was FDA-approved for melanoma in 2015.  This particular combination, and other combination immunotherapy regimens in development, is likely key to improving patient response rates.