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Vaccine and Immunotherapy Center

Massachusetts General Hospital

2018 Holiday Newsletter

First in Human

The central mission of the Vaccine and Immunotherapy Center is “to accelerate the development of novel, broadly applicable vaccines and immunotherapies for infectious diseases, cancer and type 1 diabetes.” A key transition point in the development of a new medical product is the start of clinical trials. VIC has been focused on moving promising technologies from “preclinical testing” to “clinical testing.”

This year marks the completion of a turning point for VIC as three new technologies have entered the path to first-in-human testing. In this newsletter, we bring you reports of technologies transitioning to clinical trials, along with reports of progress on several other innovative technologies developed by our scientists and supported by your generous giving.

Featured Program: First–in–Human Clinical Trial of Laser Adjuvant

Vaccines remain the safest, most efficacious and cost- effective disease–preventing medical technology ever developed. Many vaccines require something to boost the immune response to the vaccine, and some of these immune–response boosters, or "adjuvants", contribute to the pain of vaccination and to vaccination side effects, a feature of adjuvants known as "reactogenicity ". Currently most vaccinations are given as more or less painful intramuscular, or IM, shots. It has been known for years that introducing vaccine into the skin, or intradermal (ID) vaccination, requires less than half the amount of vaccine needed for IM vaccination, and causes less pain. In addition, new vaccine technologies with vaccine patches and tiny little needles that can be pressed into the skin are in development. No approved adjuvants exist for these ID or next- generation skin targeted vaccines.

VIC has been pioneering painless laser-light stimulation of the skin as an immune-stimulating vaccine adjuvant. After completing exhaustive experimentation in mice, VIC has worked collaboratively with several groups to perform the first-in-man controlled, blinded clinical trial of the laser adjuvant, the report of which has been recently published (Gelfand et al, Federation of American Societies for Experimental Biology Journal, 2018). In both human and mouse, focused illumination with the laser adjuvant stimulated migration of immune cells from the skin towards the lymph nodes, where immune responses occur. This effect can boost the immune response to an ID-delivered vaccine. A prototype clinical device, shown above, has been developed with a local Massachusetts company, Veralase, who have engineered an elegant, smaller than an iPhone, rechargeable, multi-use laser that upon mass production could be manufactured for less than the price of a stethoscope.  VIC is truly "lighting the way" towards modern, painless, potentially "needleless" vaccines to advance the prevention and treatment of infectious diseases and cancer.image.png

Donor Reflection: The Ward Family

New Paths Towards Tissue Regeneration: B Cell Immunotherapy

 VIC is continuing to develop novel cell-based treatments, using the body’s own immune cells to increase the efficiency of tissue repair. Over the past year, Dr. Ruxandra Sîrbulescu, a senior scientist at VIC and Instructor of Medicine at Harvard Medical School, has led efforts to define the ability of B cells to promote tissue healing in the context of difficult injuries. B cells are white blood cells typically known for their capacity to produce antibodies to fend off pathogens, such as bacteria and viruses. However, these cells are able to do much more under the right conditions, interacting in multiple ways with surrounding cells, greatly improving the response to injury in the process. “Essentially, we are using these cells to change the entire local microenvironment of an injury and accelerate the progress of healing”, Dr. Sîrbulescu said.

True to its mission, VIC is striving to address complications associated with diabetes, and chronic wounds are a major area of medical need. “Diabetic foot ulcers are the most common cause of non-traumatic major amputations around the world and the costliest type of chronic wound to care for, so an inexpensive and safe way to accelerate healing will have great benefits,” Dr. Sîrbulescu said. The team is in active dialog with the Food and Drug Administration (FDA) to obtain necessary approvals to isolate B cells from blood and apply them in the context of chronic wound care to accelerate healing in patients with diabetes. VIC is currently working to secure funding for a clinical trial of this novel medical technology.C:\Users\rs229\Desktop\Sirbulescu_VIC_Cutaneous nerve.tif

Also, over the past year, Dr. Sîrbulescu, a neuroscientist by training, has extended the applications of this technology to another very difficult-to-treat pathology: traumatic brain injury. “What we have observed in early preclinical studies has been a remarkable protective effect of B cells in the context of brain lesions – both brain structure and function were protected by treatment with these cells,” Dr. Sîrbulescu said. Through collaborative work with intensive care clinicians at MGH, our goal is to make this treatment a therapeutic reality for the tens of thousands of patients with severe brain injury each year.

Transplanting human stem cell derived beta cells to cure Type 1 Diabetes

Type 1 Diabetes (T1D) is a lifetime debilitating disease that is caused by immune destruction of the insulin-producing cells of the pancreas known as beta cells. There is no cure for T1D and individuals with the disease must inject themselves with insulin to control their blood sugar levels for their lifetime. These patients will still develop complications because insulin injection cannot function like normal beta cells to control blood sugar levels. Dr. David Alagpulinsa at VIC, together with the Harvard Stem Cell Institute (HSCI). is using insulin-producing cells that are made from human stem cells. The cells generated in this way are called stem cell derived beta cells or SC-beta cells. SC-beta cells can be consistently produced in large quantities which would be enough to treat every person with T1D. To protect the SC-beta cells from immune attack when they are transplanted into patients, the Alagpulinsa lab is successfully using a small protein that blocks the immune response and natural materials that are compatible with the body to encapsulate the SC-beta cells. Dr. Alagpulinsa’s laboratory has shown that SC-beta cells can cure T1D in mice.  Now, his laboratory is testing whether the SC-beta cells can cure T1D in large animals and is exploring how long these human insulin producing cells can survive and function. This exciting collaborative work with Prof. Doug Melton’s lab and with Prof. James Markmann and his team in Transplant Surgery at MGH is supported by JDRF, VIC Innovation Fund and the HSCI. IMG_1001

De-stealthing the tumor with novel immunotherapy

Dr. Huabiao Chen’s team is working on the development of novel combination immunotherapies. By combining a novel protein immunotherapy developed at VIC with other immunotherapies, they hope that they can reach the goal of tumor remission and improved patient survival. To this end, Dr. Chen’s research on the cellular and molecular level is providing insights into potential combination therapies for a variety of challenging cancers, including mesothelioma, ovarian and head and neck cancer. Funding of these combination immunotherapy studies started with philanthropic and DoD grant support for ovarian cancer, has broadened to include mesothelioma, and industry funding for work on head and neck cancer. His team is working with clinical investigators to start the first clinical trials of a combination immunotherapy in the coming year.

Dr. Chen has recently launched a new effort on mesenchymal stem/stromal cells (MSCs) as a potential cancer therapy. Under a newly awarded grant from the US Department of Defense, his team is exploring the antitumoral effects of MSCs on ovarian cancer. In initial studies they found that the VIC immunotherapy protein enhances the antitumor efficacy of MSCs by promoting conversion to a specific antitumoral cell type. This work, if successful, will add a new therapeutic regimen which may significantly prolong survival of patients with cancer.

Tao Li (PhD candidate) works on the culture of MSCs under supervision of Dr. Huabiao Chen.

In pursuit of better combination immunotherapies, Dr. Chen appreciates the importance of VIC donors to his work. “VIC support for our projects has been great, and many elements of our progress couldn’t have been made without the generous support of our philanthropic donors”.

“The project management and grant management support at VIC is unparalleled,” he adds. “Grant funding covers the experiments, but not the time spent designing ahead of time and reporting afterward. Thanks to the generosity of donors, VIC provides me with the support I need to advance my research.”

Antimicrobial blue light: tackling drug resistance without using drugs

Although microbiologists have been ringing the alarm bell for years, the threat of antibiotic resistance has reached new prominence in the popular press, gaining visibility as a looming global emergency. Antibiotic resistant infections are now as life-threatening as cancer, both in the number of cases and the likely outcome. There is a pressing need for the development of alternative treatment regimens to overcome antibiotic-resistance.

Dr. Tianhong Dai, an Assistant Professor at the Wellman Center at MGH and newly affiliated with VIC, and his team are exploring the use of antimicrobial blue light (aBL), an innovative non-antibiotic strategy, for the treatment of antibiotic -resistant infections. aBL kills microorganisms by over-exciting some of their own natural processes, and thereby acts in a manner distinct from antibiotic drugs. Dr. Dai’s team successfully carried out studies of aBL for the treatment of lethal infections in third-degree burns of mice and published a ground-breaking paper in Antimicrobial Agents and Chemotherapy (2013; 57:1238-45). They then further demonstrated the effectiveness of aBL against multidrug-resistant infections of burns. These studies also showed that the development of resistance to aBL by microorganisms is very unlikely. The team is now investigating the combined effect of aBL and other antimicrobials. Studies thus far indicate that the combination therapy using aBL and certain antibiotic compounds can increase the killing of microorganisms by up to 100,000-fold. Given the significant limitations in current treatment of antibiotic-resistant infections, this new strategy using aBL exhibits great potential, particularly for treatment of localized infections (trauma wounds, urinary tract infection, genital tract infection, etc.). The Dai team’s research has been supported by grants from the NIH and the Department of Defense, as well as by several foundations.

Delivering a one – two punch against cancer and infectious diseases

When our bodies are fighting against cancer or an infection, it is the immune system that is responsible for detecting and defending against the threat to our health.  The development of vaccines for infectious diseases has helped to uncover the fundamentals of how to effectively expand and train immune cells. This understanding gave rise to cancer treatments that reinvigorate the immune response against cancerous cells, or immunotherapy, which can provide extraordinary benefits to those patients who respond favorably. However, too many patients either do not benefit from immunotherapy or suffer from significant side effects.  This shortfall, between the potential of immunotherapy to help cancer patients and the results seen in clinic, highlights gaps in our knowledge and understanding of the intricacies governing the cat and mouse interplay between the immune system and tumors or pathogen. Dr. Patrick Reeves, a senior scientist at VIC, is working to address the gap in treatment success by developing new treatment strategies and examining the immune system in extraordinary detail to uncover the hallmarks of effective responses. Dr. Reeves is using drugs that mobilize immune cells into the tumor and limit the ability of cancerous cells, including mesothelioma, ovarian and virus induced head and neck cancer, to evade attack. The goal is to ultimately deploy both strategies in tandem to unleash an overwhelming response against the cancer.

“All of our work is focused on looking ahead and asking relevant clinical questions that will be helpful to our patients in two to three years.” Dr. Reeves says. “Donor gifts help to keep VIC in a leadership position for the effective use of this technology across the disease spectrum.”\\Cifs2\qpoznan2$\VIC--Website\Web Site Photos\Team-group photos\Team Pictures (gabby)\Patrick's Team\DSC_0929.jpg

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