Face-to-Face Communication Essay

Point 3: Do you concur or differ with the accompanying proclamation? Eye to eye correspondence is superior to different kinds of correspondence, for example, letters, email, or calls. Utilize explicit reasons and subtleties to help your answer. Various types of correspondence have been grown these days and they make it extremely simple for individuals to contact with one another. We have gotten comfortable with mainstream sorts of correspondence, for example, letters, email, calls or visiting on the web. Anyway a few people say that up close and personal talk is superior to different methods for correspondence. As I would like to think, I can't help contradicting this feeling. Because of the restriction of separation, up close and personal correspondence shows its impediments in a ton of circumstances. We can't meet and have a talk on the off chance that we are far away from one another like in various nations or various zones. It is extremely upsetting when we have to stand up something quickly or we are in a dire circumstance. Eye to eye talk truly takes a lot of time and cash if individuals are too far off. Additionally, in the quick pace of life, everybody is extremely occupied with their own work. They need to manage heaps of work and contact with a few dozen individuals. Subsequently, it is hard for them to consistently plunk down in a pleasant spot and converse with one another in light of the fact that it constrains their degree of work efficiency. Aside from separation and time, different kinds of correspondence exceed eye to eye talk regarding comfort and mystery. You can email to many individuals in various nations with just a single tick. You need to impart your joy to your companions and family members, simply get your telephone and consider them without heading over to make a declaration. At the point when you begin to look all starry eyed at and think that its hard to communicate your energy straightforwardly, at that point an affection letter to that individual will be a correct decision. With the solace of utilizing the web, we effectively make companions without being stressed over our appearances. Notwithstanding the way that we are fat or meager, pretty or terrible, perfect or careless, we despite everything have incredible talks in light of the fact that nobody sees us right at that point. All in all, up close and personal is only one type of correspondence among others. Each of those has its own points of interest and drawbacks and it is hard to state which one is better. Individuals ought to be adaptable in utilizing methods for correspondence to make our connections all the more fascinating.

The Vietnam Conflict And Its Effects Essays - Vietnam War

The Vietnam Conflict and its Effects The Vietnam struggle started in the late nineteenth century. The French vanquished Vietnam and made it a protectorate. For almost forty a long time, Vietnam had not experienced settled harmony. The League for the Freedom of Vietnam ( Viet Minh ) was shaped in 1941, looking for freedom from the French. On September 2nd,1945, Ho Chi Minh declared it free of France. The French contradicted their freedom from 1945 to 1954. The principal agents of de Gualle's administration arrived by parachute in Saigon and Hanoi on August 23rd, 1945. The French needed to restore their standard in Vietnam yet were beaten at the skirmish of Dien Bien Phu on May seventh, 1954. The French Expeditionary Force attempted to forestall the Viet Minh from entering Laos and Dien Bien Phu was the spot picked to do as such. The French were not cautious and this permitted the Viet Minh to cut off their aviation route to Hanoi. After an attack that had gone on for fifty - five days, the French gave up. Ho Chi Minh drove the war against France also, won. After the war there was a meeting in Geneva where Vietnam was separated into two sections along the seventeenth equal. North Vietnam was essentially Communist and bolstered Ho Chi Minh, while the south was upheld by the United States and the French were based there. There was still some Communist agitators inside South Vietnam. These were the Viet Cong. The South Vietnam ruler was Ngo Dinh Diem who was hostile to - Socialist. At the meeting, Laos and Cambodia got autonomous states. North Vietnam wished to bring together North and South Vietnam through military power. Since the United States dreaded the spread of socialism in Asia, John F. Kennedy gave financial and military guide to South Vietman to forestall the takeover by North Vietnam. As of now, this was as yet a common war. The United States were not yet formally included. The North Vietnamese disliked the little intercession by the Joined Sates thus, three Vietnamese torpedo pontoons terminated on the U.S. destroyer, Maddox on August second, 1964. The Maddox had been in the Gulf of Tonkin ( worldwide waters ), thirty miles off the bank of Vietnam. On August third, 1964, Johnson gave the privilege to assault with the goal of wrecking assaulting powers ( Pimlott 1982, 36 ). Counter air assaults started on August third. Their point was to wreck North Vietnam's gunboat ability. As two increasingly United States destroyers were as far as anyone knows sunk, more air and ocean powers were sent ( Wicker August 5, 1964, 1 ). As of recently, the U.S. had avoided direct battle. This is the point at which the United States officially entered the Vietman War. The U.S. did this for two reasons. We wished to keep up the freedom of South Vietnam and we needed to demonstrate to united countries that we would assist them with opposing Communist overwhelming. As Congress was going to cast a ballot whether to permit the battle to move into North Vietnam, the North Vietnamese assaulted a significant U.S. airbase at Bein Hoa. On February seventh, 1965, Johnson requested reprisal shelling on North Vietnam. Moving Thunder was the name of this activity. It's motivation was to squeezed Hanoi and persuade them that Communism couldn't and would not win. Toward the finish of 1965, one hundred and eighty thousand Americans were in South Vietnam under General William S. Westmoreland (Reference book Britannica, 12, 361 ). The U.S. primarily relied upon predominant capability and helicopters. The Viet Cong and North Vietnamese relied upon shock assault and camouflage. The United States fighters understood that the war would keep going for a lot more years and thought about whether the U.S. war exertion could succeed. At the finish of 1968, The quantity of American soldiers in South Vietnam arrived at it's pinnacle of 542, 000 men ( Pimlott 1982, 53 ). The Viet Cong what's more, North Vietnamese propelled a significant attack against the United States called the Tet hostile from January 30th to February 25th, 1968. At the Khe Sanh U.S. firebase, there was a significant ground fight. There was an attack from January 21st to April fourteenth. It was thought to be the

Writing Good Research Paper Topics About Ceramics

<h1>Writing Good Research Paper Topics About Ceramics</h1><p>Ceramics look into paper subjects are somewhat not quite the same as most science paper points. It is very regular to discover science points that are written in a standard arrangement, however they may not be the most intriguing subjects to peruse. These subjects can be fun, notwithstanding, on the off chance that you comprehend what to do.</p><p></p><p>In request to compose extraordinary earthenware production examine paper themes, it is essential to require some investment. By taking as much time as necessary, you will have the option to work through every part of your subject as it comes to you, and you will have the option to accomplish an exceptional outcome. The initial step to composing your paper, in any case, is to glance around at the various pottery books, magazines, and online sources. Ensure that you read a few distinct sources before starting your research.</p>& lt;p></p><p>Once you have taken a gander at these sources, you should choose which source will be generally valuable for you. You will likely locate that a few sources are a higher priority than others, yet they will all offer you data. Set aside some effort to peruse a portion of the accessible sources, and you will make certain to discover all the data you requirement for your exploration paper.</p><p></p><p>There are numerous incredible spots for you to begin your examination paper subjects. The exploration paper themes that I am generally acquainted with are the food and refreshments, and the existence sciences. These two territories are sweeping and furnish you with a great deal of data to work with. In spite of the fact that you will likely run over a ton of data when seeing this sort of research, you will have the option to get a decent handle on the entirety of the different subjects, just as having some extraordinary themes to expound on in the end.</p><p></p><p>If you decide to expound on earthenware production, you should remember that your examination paper points should be explicit and stick out. In any case, when you begin perusing a portion of different sorts of paper points, you will understand that you can get a great deal of data from them, and that they are less specific than the earthenware production. Notwithstanding, you can in any case get extraordinary data from the examination paper points that are progressively explicit. The upside of having a less particular point is that you will have the option to focus on the crowd that you need to get your data to.</p><p></p><p>If you have a few companions that are contemplating the existence sciences or the food and drinks, at that point there are some other extraordinary assets that will assist you with composing the best research paper subjects. They have likely been alloted their own examination paper theme that they have to follow. These kinds of research paper subjects are simpler for you to expound on the grounds that they are increasingly broad in nature. This is another motivation behind why you ought to compose an examination paper theme that is specific.</p><p></p><p>When it comes to explore paper subjects, you should realize that there are heaps of decisions to make. So as to expound on earthenware production, you can decide to utilize the entirety of the different research paper points that relate to pottery, or you can decide to compose a particular research paper theme that relates to earthenware production. There are a couple of various choices that you can browse. Regardless of what sort of earthenware production look into paper subjects you decide to compose, you will find that you have the whole range of conceivable outcomes that you can pick from.</p><p></p><p>In request to compose the best research paper points, you ough t to consider the entirety of the examination paper themes that relate to your preferred subject. On the off chance that you utilize this system, you will have the option to compose the ideal research paper theme for the particular subject that you need to discuss. Attempt to get a few thoughts for look into paper points, and afterward survey every one of them until you have the entirety of the data that you need. This is the most ideal approach to truly do a careful research paper topic.</p>

What You Do Not Know About Global History Regents Thematic Essay Topics

<h1> What You Do Not Know About Global History Regents Thematic Essay Topics </h1> <p>Scroll through the assignments to find the test you're looking for. Envision you have to create an overall officials topical paper and you have 3 days accessible. Indeed, even in the occasion the cutoff time is in reality close, don't hesitate to get hold of our directors. </p> <p>Since you're dealing with a topical activity, you generally should adhere to the development of the significant target. Your motivation is to compose a compact survey of the activity you've just never really clear each point that is very critical for your paper. In any case, you ought to learn different necessities on the off chance that you might want to make a reasonable venture. Be consistent and intelligible while giving your significant considerations and ideas. </p> <h2> Global History Regents Thematic Essay Topics - Overview</h2> <p>The details associated with ke eping a predominant topography topical paper while as yet adhering to all the linguistic standards, accentuation rules and the basic data is somewhat requesting. In spite of the fact that it has a few likenesses with other article types, there are a couple of urgent contrasts moreover. At the point when you start composing a topical paper, you can promptly become mixed up in different parts, sources, and contentions. You need to utilize proficient sources, and apply different abstract practices. </p> <p>There are no exacting standards about the span of the presentation, however you should mull over the time of your paper when composing it. There is a decent determination of subjects that might be utilized to make great parts out of scholastic composition. The configuration of paper can't be chosen noticeable all around with no decent base like what is the length of article as indicated by the directions of the teachers. You should be cautious while choosing your topics. </p> <p>An paper can't be cleaned enough. Whatever it is that you have to expound on, you have to watch your topical exposition is written in a reasonable technique. Finally, an amazing topical article consistently has a fairly solid end. For instance, you are mentioned to compose 500 words paper looking like the topical article at that point it will be diverse when contrasted with a protracted exposition. </p> <p>There are various kinds of papers. The main issue is you ought to find how to make a topical paper. </p> <h2> Get the Scoop on Global History Regents Thematic Essay Topics Before You're Too Late </h2> <p>Thematic articles are normally to some degree long, so it's not irregular to get numerous unmistakable sections to investigate loads of remarkable focuses. For example, you may choose the noteworthy actuality or a social issue for a subject for your exposition. Thus, you should pick an adequate point, relying on a planned peruser. Ensure your acquaintance furnishes the reaction with the inquiry. </p> <h2> Global History Regents Thematic Essay Topics Secrets That No One Else Knows About </h2> <p>Your essential undertaking is to altogether take a shot at every region of the exposition so as not to miss anything. There are the individuals who don't have even thought regarding choosing and discovering a suitable point for topical e xposition and such alumni need to find the assistance of master article essayists in such an accommodating recommendations. You will have away from of the best approach to assemble the whole staff. Addresses all subtleties of the undertaking. </p> <p>Theme expositions are believed to be the easiest to compose. Last, you should assemble an a theory proclamation that is as per the focal subject of your paper. Topic is the beat of the story and should you pick accurately you will feel constrained (in an extraordinary method) to complete your story. You need to need to or even need to investigate that particular topic for you to keep composing. </p> <p>Creating such an artistic work is no straightforward accomplishment. Presentation is the focal point of each exposition. The presentation of the article is the part which shows up in the beginning. </p> <h2> The Tried and True Method for Global History Regents Thematic Essay Topics in Step by Step Detail </h2> <p>Another thing that is consistently brilliant to do is to discover another person to peruse your paper. Whatever it is that you mean on discussing, you should talk about focuses that are easy to analyze without being excessively extreme. If all else fails search for the most consistently raised idea, and you'll find the core of the article. On the off chance that you are pondering where to get this sort of model that is additionally unique, you've shown up at the most reasonable spot. </p>

Top Research Paper Topics 9th Grade Reviews!

<h1> Top Research Paper Topics ninth Grade Reviews! </h1> <p>Brainstorming exercises may give assistance. One of the most troublesome undertakings for understudies is concocting reasonable and instructive points. In case you're keen on your subject, finding out about it will be progressively pleasurable and you'll compose with expanded enthusiasm, so select your point attentively. English language classes for the most part need a great deal of composing. </p> <h2> The Foolproof Research Paper Topics ninth Grade Strategy </h2> <p>Locating a decent subject is only one of the principle steps when composing any kind of paper. By investigating an elegantly composed instance of research proposition paper, you will discover that themes which are too wide can be trying to oversee as you will most likely have unique, and every now and again clashing, thoughts regarding how to handle the issue. When you have an idea of what you wish to expound on, guar antee your subject is neither expansive nor restricted. Presently you have a thought about what a proposition exposition is and the best approach to pick the perfect subject to create your own article, here are a couple of instances of proposition exposition topics.</p> <p>With regard to understanding, working with someone who has taken a shot at comparable papers implies they comprehend the necessities and rules. A total contextual analysis might be the African-American social equality development. On the off chance that you think about research for an inquiry to respond to an inquiry, you are not just going to be increasingly disposed to discover progressively helpful information, you'll additionally be not as liable to become overpowered by your pursuit approach. You ought to likewise consider getting master help in the event that you come up short on the abilities to research and figure an educational and sensible subject without anyone else. </p> <p>A pa per is constantly easier to compose in case you're keen on this issue, and you'll be progressively persuaded to do top to bottom research and form a paper that really covers the full subject. Pugnacious papers are a structure and type of an exposition that should contend a specific thought or idea that is then brought through a procedure which offers backing and information that could improve or detract from the perspective on the situation. On the contrary edge, the exploration exposition subject ought to be one which your perusers will find simple to grasp. Likewise you may utilize the absolute best case of interpretive article. </p> <p>Attempting to create an examination paper on a subject that doesn't have a ton of research on it's unimaginably hard, so before you pick a point, do a smidgen of fundamental looking and be certain you will have all the data you need to form your paper. At that point find more by looking at the on-line segment of neighborhood and national papers where you can find out about wrongdoing or legislative issues. Each American ought to figure out how to communicate in English. </p> <p>You can both use individual experience and spread new subtleties for you, contingent upon the exploration of various writers and making your very own determinations. On the off chance that you select a theme that hasn't been highlighted in a hundred of other research papers, you're likely to score an extraordinary evaluation, however moreover to include an important cut of research to the zone of science. You should seriously think about history for a part of study that falls from the domain of social examinations. Each American ought to figure out how to communicate in Spanish. </p> <p>Not all exploration paper themes are made equivalent, and you might want to verify you pick an awesome subject before you start composing. At the point when you have chosen your subject of research, create foundation data about that theme to widen your mastery and to improve cognizance of data that might be included your examination. You've looked to a great extent to find a worth y point for examine yet the entirety of your endeavors have gone futile. You have to attempt to pick a theme for your examination subject in accordance with the directions of your educator. </p> <p>Choosing points for examine papers can take some second, and here are two or three different ways to assist you with choosing the one which is simply great. Scholastic papers can't contain any signs of counterfeiting. Research papers are proposed to assess and survey the cognizance of understudies in some particular points. Composing research papers is a wearying strategy, and considerably more so at whatever point you don't have a foreordained theme. </p>

College History Essay Topics

<h1>College History Essay Topics</h1><p>College history paper points are key components in any secondary school understudy's course work. They assist understudies with remaining focused and make their scholarly examinations more appealing.</p><p></p><p>It is a typical misguided judgment that the themes in secondary school courses are unimportant; even among educators. The genuine truth is that understudies and instructors invest a ton of energy talking about what each subject is about, how it has developed after some time, and how it influences present day society. So by rounding out these sorts of papers understudies can improve thought of the past and anticipate the future.</p><p></p><p>Teachers discover this kind of composing supportive as they get a chance to give understudies a point by point knowledge into the authentic foundation. Furthermore they additionally see this as an opportunity to really discover progre ssively about the past themselves and recognize what they are truly discussing when they notice explicit dates or events.</p><p></p><p>Unfortunately, there are many sites out there that offer school history exposition subjects that are cockeyed or ineffectively composed. By perusing the substance of a portion of these destinations you can see the mix-ups they leave just as why these slip-ups occur.</p><p></p><p>A normal mix-up made by numerous scholars is to attempt to make a secondary school subject sound like a significantly more testing or propelled subject, for example, an AP English Literature paper for instance. This is the greatest misstep you can make. This will never enable your evaluation to point normal in any capacity and may even mischief your grade.</p><p></p><p>Another botch made by numerous scholars is to likewise incorporate data about different regions of study, for example, a science course or an aesthetic sciences course, all of which majorly affect your evaluation as far as school history article subjects. Rather, focus on each territory in turn and not really put a lot of data into a whole.</p><p></p><p>In request to abstain from having any of these kinds of papers in your transcript, it is imperative to just utilize one theme for each two pages. This will help you in two different ways: one, it will assist you with your general evaluation and two, it will help your material stick out.</p><p></p><p>Good history paper subjects for school will have the option to let your understudy see increasingly about the past and better set them up for life later on. Get your work done appropriately and your understudies will adore your class and your composed materials!</p>

Treatment of Solid Tumors including Metastatic Breast Cancer - Free Essay Example

Citizen Petition Reconsider Issuance of RMAT Designation for Therapeutic Armed Activated T Lymphocytes Treatment of Solid Tumors including Metastatic Breast Cancer The undersigned submits this petition under to request the Commissioner of Food and Drugs to reconsider issuing a Regenerative Medicine Advanced Therapy (RMAT) designation to autologous T-lymphocyte therapies for patients with malignant advanced stage solid tumors, specifically stage IV metastatic breast cancer, on the basis that it can meet an unmet medical need as substantiated by new clinical trial evidence resulting from trial involving OKT3 x Herceptin Armed Activated T Cells, Low Dose IL-2, and GM-CSF, as relevant to section 506(g) of the Federal Food, Drug, and Cosmetic Act (FDC Act), as added by section 3033 of the 21st Century Cures Act (Cures Act). A. Action Requested The Expedited Programs for Regenerative Medicine Therapies for Serious Conditions Draft Guidance for Industry states that in order for an investigational drug to receive a Regenerative Medicine Advanced Therapy (RMAT) designation it must fulfill the following criteria1:. It meets the definition of regenerative medicine therapy (see section I of [draft guidance] document) It is intended to treat, modify, reverse or cure a serious condition; and Preliminary clinical evidence indicates that the regenerative medicine therapy has the potential to address unmet medical needs for such condition The Expedited Programs for Regenerative Medicine Therapies for Serious Conditions Draft Guidance for Industry states that the definition of regenerative medicine therapy is1: †¢ Cell therapies, therapeutic tissue engineering products, human cell, and tissue products, and combination products using any such therapies or product And Gene therapies, including genetically modified cells, that lead to a durable modification of cells or tissues may meet the definition of a regenerative medicine therapy. In said draft guidance, unmet medical need is defined as: †¢ An unmet medical need is a condition whose treatment or diagnosis is not addressed adequately by available therapy. An unmet medical need includes an immediate need for a defined population (i.e., to treat a serious condition with no or limited treatment) or a longer-term need for society (e.g., to address the development of resistance to antibacterial drugs). We, the undersigned, petition the Commissioner of Food and Drugs to reconsider issuing an RMAT designation to autologous T-Lymphocyte therapies for solid tumors, and we offer new clinical trial data from the trial named Treatment of Stage IV Breast Cancer With OKT3 x Herceptin Armed Activated T Cells, Low Dose IL-2, And GM-CSF (NCT00027807) as clinical evidence that indicates the potential to meet an unmet medical need thereby fulfilling the requirement â€Å"that the regenerative medicine therapy has the potential to address unmet medical needs for such condition† listed in The Expedited Programs for Regenerative Medicine Therapies for Serious Conditions Draft Guidance for Industry.1 B. Statement of Grounds Cancer is the second leading cause of death in the United States, with breast cancer following lung cancer as cancers with the highest mortality rates. While there have been a number of cancer therapies found to either treat or cure early-stage cancers, late-stage solid t umors tend to elude these therapies, and as a result, there are very few therapies that can attempt to treat them. Breast cancer is a disease that affects 1 out of 8 women, with 10% of all cases eventually metastasizing 5 years after the patient has received therapy for it.2,3 Many patients receive a form of therapy for breast cancer that may involve surgery with adjuvant chemotherapy, or even in the case of high-risk breast cancer high-dose chemotherapy with a stem cell transplant. Unfortunately, relapse rates after these therapies remain high, and often times the cancer has metastasized at that point. 55-87% of women who have primary breast cancer with 10 or more axillary lymph nodes relapse within 5 years of when they were diagnosed. 4 Stage IV metastatic breast cancer represents an unmet medical need, as it is not being met by current treatments or therapies. Additionally, there is research that indicates that combination therapies would work in a more effective manner against metastatic breast cancer than a single therapy.4 Some of the therapies that are currently being considered in clinical trials involve chimeric T cells, others are looking at armed activated T cells (aATC), and others are considering antibodies.3,4 The trial in question that we are using as the basis for our petition analyzes the combination immunotherapy consisting of HER2Bi armed activated T cell infusions, IL-2, and GM-CSF.3,4 The HER2Bi or BsAb consists of two monoclonal antibodies that were heteroconjugated and used to arm the T cells. These two monoclonal antibodies were Trastuzumab (Herceptin, Genentech) and an anti-CD3 (OKT3, Centocor, Ortho-Biotech) that were prepared under Current Good Manufacturing Practice (cGMP) regulations as enforced by the Food and Drugs Administration.5 Trastuzumab or the brand name Herceptin has been approved for use in the treatment of breast cancers that overexpress the HER2/neu receptor, which is a tyrosine kinase transmembrane epidermal growth factor receptor family member.3 The HER2/neu receptor is overexpressed in many breast, ovarian, gastric, lung, prostate and oral cancers. This overexpression of HER2/neu makes it an ideal therapeutic target. 3,4 Moreover, women with HER2- cancers have fewer therapeutic options, but the trial demonstrated a positive result in those patients as well, which further supports the claim that this therapy can fulfill an unmet need for a serious condition. The OKT3 or anti-CD3 antibody targets the CD3 T cell receptor. Together they form the HER2 Bispecific antibody (HER2Bi), which is engineered to direct cytotoxicity at tumor cells that overexpress the HER2/neu receptor. In this trial, they combined the HER2Bi with Interleukin-2 and the granulocyte macrophage colony-stimulating factor (GM-CSF). Interleukin-2 is a cytokine produced by leukocytes, which increases the growth and activity of other T lymphocytes and B-lymphocytes, as well as affecting the development of the immune system. GM-CSF is another cytokine that helps create additional white blood cells specifically granulocytes, macrophages, and cells that become platelets.3 The primary endpoints of the trial were to determine the safety and maximum tolerated dose. The highest dose that was administered consisted of 20 x 10^9 aATC, and the maximum tolerated dose level was not reached, nor were there any dose-limiting toxicities observed at this dosage level. The secondary endpoints of the study were assessments of response rates: complete response (CR), stable disease (SD), partial response (PR), and no evidence of disease (NED), time to progression (TTP), and overall survival (OS). TTP and OS were measured from the date of enrollment in the trial.3 The study consisted of 23 women with stage IV metastatic breast cancer, of both HER2+ and HER2- patients, in a traditional 3+3 dose escalation design. One patient in the study died from digoxin toxicity related congestive heart failure, and the autopsy of the patient did not show any myocardial T cell infiltrates. The remaining 22 patients were evaluated at 14.5 weeks. Results showed 59.1% (13/22) of patients had SD or better (NED, PR, or SD) and 40.9% (9/22) of patients had PD. The overall survival rate of the 22 evaluable patients was 36.2 months. Within the overall survival rate, the breakdown was an overall survival rate of 57.4 months for HER2+ and 27.4 months for HER2-. The results of t his study showed that there were no major negative side effects associated with this aATC therapy. There were no cytokine storms, which has been a problematic side effect in past T-cell therapies, but there were however what the researchers designated cytokine flurries.3 And while a number of patients had to have their aATC washed to reduce side effects, not a single patient had to have their dose lowered. The main side effects observed were grade 3 chills and grade 3 headaches. The incidence of chills was 8.6%, 20.8%, and 43.1% at dose levels 1, 2, and 3, respectively. The incidence of headaches was 3.1%, 8.3%, and 19.6% at dose levels, 1, 2, and 3. Two patients were hospitalized to manage other side effects that included nausea, hypotension, vomiting, and dehydration, but after the successful resolution of these side effects they resumed the trial and continued to receive the infusions of the aATCs. In this trial, the innate cytotoxicity of T cells was redirected by the formation of the aATC (can be prepared with either CD4+ or CD8+,). Normal patients and cancer patients who rec eived this combination therapy of aATC with HER2Bi combined with IL-2 and GM-CSF both exhibited specific cytotoxicity towards target cells, and the cytotoxicity increased as the dosage amount of the aATC increased. 4 The cytotoxicity persisted for more than 54 hours towards the target cells, and other cytokines including IFN-?, TNF- ?, and GM-CSF were induced when the tumor antigen was bound to the aATC.4 This capability of the aATC to induce IFN-? when it binds to a tumor antigen may be clinically beneficial, as other studies have already shown in preclinical and clinical studies that cytotoxic T cells produce IFN-? and that IFN-? is tumoricidal.6,7 Another advantage of this particular therapy is that it does not require large quantities of HER2Bi unlike other infusional therapies that do require large doses of bispecific antibodies. In fact, billions of armed activated T cells can be armed with just milligrams of the HER2Bi antibody. The aATCs proved to be cytotoxic even towards breast cancers that had a low expression level of HER2 receptors, such as the MCF-7 breast cancer cell line. 4 The SK-BR-3 cell line, which has higher levels of HER2 receptors, had even more susceptibility to cytotoxic effects from the aATC, causing greater amounts of tumor cells to be lysed.4 This indicates that even a small amount of the combination of the anti-CD3 and anti-HER2 antibodies that are used to arm activated T cells can mediate high levels of cytotoxicity that is directed at tumor cells. Even when the levels of the tumor antigen expression is low as in the case of the MCF-7 cell line, and are able to mediate cytotoxicity in vivo for many days after infusion of the aATCs.4 The fact that that the maximum tolerated dose was not reached, that there were no dose-limiting toxicities, nor was there any evidence of a life-threatening cytokine storm, and all other side effects were relatively mild and successfully resolved supports the idea that multiple infusions of aATC in combination with IL-2 and GM-CSF were both safe and technically feasible. The results of this study showed that combining antibody targeting and T cell-mediated killing could greatly augment cytotoxicity that can be directed towards cancer cells and provides a rationale to develop new nontoxic immunological approaches that can eradicate any residual tumor cells. 4 Ultimately the researchers have concluded that multiple intravenous infusions of the HER2Bi aATC are feasible, and most of them would go to the lungs and then migrate to, and settle, in the spleen, bone marrow, and liver. This is advantageous because many breast cancers metastasize to these locations, which would make the targeting of these metastases by the aATC easier. The authors of this study had intended on moving forward with a Phase II trial, and the results supported the rationale for moving forward. However, this trial ultimately did not move forward to a Phase II trial, but it did provide the rationale for further clinical trials on similar immunotherapies. A separate trial studied the HER2Bi armed activated T cells in HER2+ colorectal cancer, both in vitro and in vivo. The aATC exhibited increased cytotoxicity against HER2+ tumor cells, and showed significant suppression of colorectal carcinoma cells in comparison to unarmed ATC. Similar to the above-mentioned breast can cer trial, researchers were able to reach these results by using a very low dose of HER2Bi, which eliminated previously seen side effects of Herceptin which included cardiotoxicity that manifested as left ventricular dysfunction and heart failure in a different research project. 8 Much like the trial conducted on metastatic breast cancer, the data in this trial also showed that aATC induced IFN-? secretion levels that were higher than those induced by unarmed ATC, As such the researchers of this trial concluded that â€Å"HER2Bi?armed ATCs with anti?tumor effects may provide a promising immunotherapy for colorectal carcinoma for the future†.9 Another Phase I trial examined the HER2Bi aATC in metastatic castrate-resistant prostate cancer. They also found an increased level of IFN-? as well as no dose-limiting toxicities that were associated with this immunotherapy. 3 out of 7 patients in this trial showed a decrease in their prostate-specific antigen (PSA) and pain levels. The results of this trial provided strong rationale to continue onto a Phase II trial.10 Furthermore, there is another trial in progress that is also researching HER2Bi armed activated T cells combined with pembrolizumab, which blocks the PD-1 pathway, in patients with metastatic bre ast cancer. The trial (NCT03272334), sponsored by the University of Virginia is currently recruiting patients, but we look forward to seeing if it reaches its primary endpoints, which are evaluating the side effects and best dose for this treatment without reaching any dose-limiting toxicities. 11 While we need to keep a watchful eye on more severe side effects such as the possibility of life-threatening cytokine storms in future trials, the fact that the trial on metastatic breast cancer only had cytokine flurries is an encouraging sign. Novel immunotherapies including T-cell therapies are making headway as therapeutics for solid tumors and is a field that holds great promise because it can boost patients preexisting tumors responses, in a nontoxic manner, specifically in tumors that have no current successful therapy options.12 We would request that the Commissioner of Food and Drugs reconsider issuing an RMAT designation to autologous T-Lymphocyte therapies for solid tumors based on the preclinical trial data as covered above from the trial Treatment of Stage IV Breast Cancer With OKT3 x Herceptin Armed Activated T Cells, Low Dose IL-2, And GM-CSF (NCT00027807). We feel that this data, along with the fact that metastatic breast cancer is a serious condition that has very few therapies available to treat, and as such is an unmet medical need, fulfills all the requirements of an RMAT designation which are listed as: It meets the definition of regenerative medicine therapy (see section I of [draft guidance] document) It is intended to treat, modify, reverse or cure a serious condition; and Preliminary clinical evidence indicates that the regenerative medicine therapy has the potential to address unmet medical needs for such condition C. Environmental Impact The petitioner hereby states that the action requested in this petition will have no environmental impact and that, therefore, an environmental assessment is not required under 21 CFR 25.30. D. Economic Impact Not applicable; this section has not been requested by the Commissioner. E. Certification The undersigned certifies, that, to the best knowledge and belief of the undersigned, this petition includes all information and views on which the petition relies, and that it includes representative data and information known to the petitioner which are unfavorable to the petition. References 1. Food and Drug Administration. (2017, November). Expedited Programs for Regenerative Medicine Therapies for Serious Conditions Draft Guidance for Industry. Retrieved December 11, 2018, from https://www.fda.gov/downloads/biologicsbloodvaccines/guidancecomplianceregulatoryinformation/guidances/cellularandgenetherapy/ucm585414.pdf 2. American Cancer Society. (n.d.). How Common Is Breast Cancer? Retrieved from https://www.cancer.org/cancer/breast-cancer/about/how-common-is-breast-cancer.html 3. Lum, L. G., Thakur, A., Al-Kadhimi, Z., Colvin, G. A., Cummings, F. J., Legare, R. D., . . . Rathore, R. (2015). Targeted T-cell Therapy in Stage IV Breast Cancer: A Phase I Clinical Trial. Clinical Cancer Research, 21(10), 2305-2314. doi:10.1158/1078-0432.ccr-14-2280 4. Sen, M., Wankowski, D. M., Garlie, N. K., Siebenlist, R. E., Epps, D. V., Lefever, A. V., Lum, L. G. (2001). Use of Anti-CD3 Ãâ€" Anti-HER2/neu Bispecific Antibody for Redirecting Cytotoxicity of Activated T Cells Toward HER2/ neu Tumors. Journal of Hematotherapy Stem Cell Research, 10(2), 247-260. doi:10.1089/15258160151134944 5. Center for Drug Evaluation and Research. (n.d.). Manufacturing Facts About the Current Good Manufacturing Practices (CGMPs). Retrieved from https://www.fda.gov/drugs/developmentapprovalprocess/manufacturing/ucm169105.htm 6. Ogawa M, W-G Yu, K Umehara, M Iwasaki, R Wijesuriya, T Tsujimura, T Kubo, H Fujiwara and T Hamaoka. (1998). Multiple roles of interferon-gamma in the mediation of interleukin 12-induced tumor regression. Cancer Res 58: 2426–2432. 7. Quian J-H, JA Titus, SM Andrew, D Mezzanzanica, MA Garrido, JR Wunderlich and DM Segal. (1991). Human peripheral blood lymphocytes targeted with bispecific anti- bodies release cytokines that are essential for inhibiting tumor growth. J Immunol 146:3250–3256. 8. Babar, T., Blomberg, C., Hoffner, E., Yan, X. (2014). Anti-HER2 Cancer Therapy and Cardiotoxicity. Current Pharmaceutical Design,20(30), 4911-4919. doi:10 .2174/1381612820666140604145037 9. Han, H., Ma, J., Zhang, K., Li, W., Liu, C., Zhang, Y., . . . Gao, B. (2014). Bispecific anti-CD3 x anti-HER2 antibody mediates T cell cytolytic activity to HER2-positive colorectal cancer in vitro and in vivo. International Journal of Oncology,45(6), 2446-2454. doi:10.3892/ijo.2014.2663 10. Vaishampayan, U., Thakur, A., Rathore, R., Kouttab, N., Lum, L. G. (2015). Phase I Study of Anti-CD3 x Anti-Her2 Bispecific Antibody in Metastatic Castrate Resistant Prostate Cancer Patients. Prostate Cancer,2015, 1-10. doi:10.1155/2015/285193 11. ClinicalTrials.gov. National Library of Medicine (U.S.). (n.d.). Her2-BATS and Pembrolizumab in Metastatic Breast Cancer (Breast-47)r. Retrieved from https://clinicaltrials.gov/ct2/show/NCT03272334 12. Melton, C. (2018, November 28). Novel T-Cell Therapies Make Inroads Into Solid Tumors. Retrieved December 17, 2018, from https://www.onclive.com/publications/oncology-live/2018/vol-19-no-22/novel-tcell-therapies-make-i nroads-into-solid-tumors?p=1