Using CAR T-cells as an Effective Tool Against Blood Cancers

Author: Peg Harley

School/Organization:

Charles W. Henry School

Year: 2021

Seminar: Cancer Biology and Technology

Grade Level: 5

Keywords: blood cancer, body systems, breakthrough, cancer cells, CAR T cells, immune system, immunotherapy, life science, T-cells

School Subject(s): Science

This unit is designed for use in a middle school science classroom.  This content would fit nicely with a study on the body’s systems and connect it to the immune system.  Students will investigate how the body’s T-cells work.  Students learn that scientists have capitalized on the T-cells as a blood cancer treatment by harvesting a patient’s T-cells and genetically engineering them to become assassins directed at the cancer cells in the body.

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Full Unit Text
Content Objectives

Middle school students in the School District of Philadelphia gain a basic understanding of cell theory and genetics in their 8th grade Science class, but they know almost nothing about the specialized functions of T-cells in the body. 8th grade students in the School District of Philadelphia focus their science learning on a Life Science curriculum.  We start the year studying cells and cell functions. Then, students learn about cell theory and genetics, as well as the function of body systems. It is interesting content, but it can be improved and offer more information relevant to disease.

I will add this unit of study about specialized T cells at the end of the current 8th grade content’s course.  In 8th grade, students will have a proficient understanding of basic genetics and how different systems of the body operate and interact. This will be an ideal jumping off point for this unit- the normal function of T-cells in the body and how this can be exploited as an effective cancer-fighting tool. This unit will connect our classroom learning to state-of-the-art cancer treatment/therapy.

I am comfortable presenting the 8th grade science curriculum as it is, of course.  However, it will be a much more powerful learning experience after I add what I’ve learned through the Cancer Biology & Technology seminar.  I have been absolutely fascinated by the content material and I can’t wait to share it with my students!

Students are comfortable with their understanding of how body systems interact. They have mastered the idea that there are specialized cells present in the body to perform certain tasks.  We will start our study off using the standard School District of Philadelphia curriculum.  That means we will begin with cells and cell functions, move into body systems and when discussing the immune system will go into more details of the broad classes of immune cells leading to an in-depth discussion of T cellsWe will use that knowledge as an entry point into a more in-depth study of T Cells and their fascinating role in Covid-19 vaccines and their role in cancer treatment as a class of therapy known as immunotherapy.

Students will understand that T cells are part of a human’s immune system.  They understand that the immune system works to protect the body from outside invaders.  The immune system protects the body from germs (bacterial and viral) that are introduced from outside the body.  Students will learn that T cells are part of the body’s most specialized cells.  T cells have a variety of roles and are classified by subsets. T cells are divided into two broad categories: CD8+ T cells or CD4+ T cells, based on which protein is present on the cell’s surface. T cells carry out multiple functions, including killing infected cells and activating or recruiting other immune cells (https://www.niaid.nih.gov/research/immune-cells).

Students will acquire the knowledge that human T cells are now part of a fascinating new tool in the cancer-fighting arsenal called chimeric antigen receptor T cells (CAR T). (https://www.cancer.gov/publications/dictionaries/cancer-terms/def/car-t-cell-therapy).  CAR T therapy is a relatively new immunotherapy where T cells are harvested from a cancer patient’s own body. These cells are then genetically engineered to become a specialized weapon in the patient’s body to eradicate the patient’s cancer.  After the T cells are harvested and expanded in the laboratory, they are reintroduced into the patient.  The CAR T cells get right to work! They are “set loose like an army of tumor assassins…A single one can destroy up to 100,000 cancer cells.” 1 The CAR T-cells are now on a mission to seek and destroy cancer cells in a patient’s body. Thus far, CAR T-cell therapy has been most effective against blood cancers that circulate throughout the body as compared to solid tumors, which grow in a specific organ such as breast or lung cancer.

I have gained a much greater understanding of the importance of T cells in the body as part of our immune system; the ability for CAR T cells to ‘cure’ blood cancers and change the trajectory and survival of a terminally ill person is astonishing.  This unit will be one that my students will remember for a long time.

This new immunotherapy has been shown to be quite effective.  Students will understand that this therapy has been able to completely eradicate certain types of blood cancer from patients.  They will read the case studies of Emily Whitehead and William Ludwig to make connections with real life people who have benefitted from this therapy.  Both of their stories are amazing and really bring the power and importance of this specialized cancer treatment to life!

The development and application of using T cells as therapy began in labs around the country but one of the first patients who were treated with CAR-T therapy occurred in Philadelphia and involved a patient named Emily Whitehead who was a young girl battling acute lymphoblastic leukemia (ALL). Standard treatments for ALL had not been successful and her prognosis was dim.  She was at the Children’s Hospital of Philadelphia (CHOP) when Dr. Stephen Grupp suggested they attempt a T cell therapy, CAR-T 19 specifically. This had not been used on humans up to this point- but Emily’s situation called for drastic measures.  This new treatment called for T cells to be harvested and then engineered in the lab to kill ALL cells by targeting a protein called CD19 on the ALL cells. Thus, the name CAR-T19 was given to these engineered T cells.

The treatment was administered, and Emily’s conditioned became more tenuous overnight. She was placed on a ventilator to facilitate her breathing.  It was found that after Emily was treated with CAR-T 19 cells, the T cells began to kill the cancer cells but it caused Emily’s body to produce too much of a particular protein that was causing her to become very sick because the levels of this protein were too high. However, there were drugs available to counteract this protein which led to a dramatic and almost overnight improvement in Emily’s condition.  Testing showed that after three weeks, she was in complete remission. Emily and CAR-T cell therapy have survived for over 10 years.

Another case study that I will share with my students is that of William Ludwig.  He was also a patient who had been treated for a different type of blood cancer called chronic lymphocytic leukemia (CLL) but his treatment was unsuccessful.  Bill lived in New Jersey but traveled to the University of Pennsylvania Hospital for treatment.   He was recommended for a clinical trial for an immunotherapy treatment. Like Emily Whitehead, Bill Ludwig had a grim diagnosis.  Ludwig was connected to Dr. Carl June and Dr. Bruce Levine who had been developing this treatment- Bill was their first patient.  Bill’s T Cells were harvested and engineered with the CAR (Chimeric Antigen Receptors) gene.  This modification allowed the CAR T cells to recognize the leukemia as the enemy and destroy them. Ludwig received a number of the CAR T cell infusions during his hospital stay.  He had a similar reaction as Emily- and initially his doctor was unsure he would survive.  But he improved greatly overnight.  A biopsy taken a month after his infusions indicated that the cancer was completely gone from his body.   William Ludwig continued to live many healthy years after this treatment.

These case studies will make the CAR T cell treatments relevant and relatable to my students. They both highlight patients who are from the area and have documented treatments and remarkable recoveries attributed to this relatively new therapy.  The students will track Emily and Bill’s disease and subsequent treatment from beginning to end.

CAR T cells are effective because they capitalize on their natural functions as part of the body’s defense system.  T cells routinely search and destroy foreign bodies such as bacteria, viruses, and other illnesses that present as abnormal including cancer cells. Genetically engineered CAR T cells are primed to attack and destroy cancer cells that have appeared in a patient’s blood by targeting a specific protein expressed on the cancer cell surface.

Mutations are another topic that is covered in our current 8th grade Science Curriculum.  Mutations are when a gene sequence changes in an organism.   Mutations can be viewed as beneficial or harmful to an organism.  Harmful mutations in an organism could include some genetic diseases or cancer itself.  Cystic Fibrosis and sickle cell are other examples of harmful mutations that occur in the human body.  T cells that have been modified into CAR T cells (Chimeric Antigen Receptors) would be an example of a beneficial mutation.  The modified cells are now able to eliminate cancer cells with surprising accuracy.

Immune checkpoint inhibitors also play a part in fighting cancer.  “Their role is to prevent an immune response from being so strong that it destroys healthy cells in the body.” (https://www.cancer.gov/about-cancer/treatment/types/immunotherapy/checkpoint-inhibitors)  In the body, sometimes T cells bind with other proteins on a partner cell called an antigen presenting cell or APC which then maintains T cell activation. If the other cells are tumor cells, this can send an “off” signal to the T cells.  This signal can “prevent the immune system from destroying the cancer. (cancer.gov) Researchers have developed immune checkpoint inhibitors that block the T cells from receiving the “off” signal when the proteins bind.  T cells remain functional and are still capable of eradicating the cancer cells. Currently CAR T cell therapy has been primarily effective with blood cancers. In contrast, the immune checkpoint inhibitors are able to attack many different kinds of tumors, including solid tumors. Examples of the cancer types might be- liver cancer, skin cancer, breast cancer.  This is another innovation in the treatment of cancer.

T cells are also effective in fighting infections in the body, like SARS-CoV-2, which is a topical discussion.  Sunil Kumar Saini, et al states, “T cells are important for effective viral clearance, elimination of virus-infected cells and long term-disease protection”.  T cells are white blood cells and their normal function is to fight infections.  They alert other cells in the body when it is time to engage “an enemy” and can also direct other cells when the fight to clear the ‘enemy’ or infection is over.  T cells identify, fight and eliminate infected cells in the body.  This has been helpful when an individual is infected with SARS-CoV-2. The National Institute of Health shared a study led by Dr. Dan Barouch of Beth Israel Deaconess Medical Center that utilized monkeys in a preclinical trial.  Antibodies were collected from monkeys that had recovered from SARS-CoV-2 and injected into unexposed monkeys.  The injected group was not subject to serious infection when later exposed to the virus.  The level of infection was linked to the level of antibodies received by the monkeys.  The study findings report that the monkeys were given either low, mid or high doses of the antibodies.  “The highest dose proved to be the most effective at reducing levels of the virus.” (nih.gov) This same study notes that monkeys who had their T cells depleted by drugs and then were reinfected with the virus and those monkeys had evidence of reinfection.  That was not the case with the monkeys who still had abundant levels of T Cells.  The findings of this study help to communicate the importance of T cells as a defense against infection.  The monkeys with the active T cells were able to combat the reinfection, while the monkeys with the compromised immune systems demonstrated reinfection.

 

Teaching Strategies

After complete this unit, will have a deep understanding of how the human body’s immune system protects the body from viruses and other foreign invaders, including cancer.  Students will be able to explain how T cells work and how genetically engineered CAR T cells interact with blood cancer cells.  They will be able to cite evidence of how this works and refer to data to support their conclusions.

Generally speaking, students become more engaged in their learning when there are involved with interactive tasks.  For this unit, we will be using graphic organizers, building models and writing a short story or a cartoon storyboard to help focus and share our learning.  We will be examining cells and identifying cell parts with our microscopes.  This will help students become engaged with their learning and enable them to synthesize and demonstrate their learning through these activities.

Graphic organizers will help students focus what they know about T and CAR T cells.  This will make composing an essay about their learning easier and more organized. Much knowledge about this topic will be new, so having graphic organizers around will help with understanding the function and use of T-cells/ CAR T-cells.

It is also beneficial to have visuals of what we are learning. Students will create models of T cells and indicate how they function in the immune system.  This will help cement their understanding of the T cell function.  We will then move into the design behind Chimeric antigen receptor (CAR) T cells.  We will share a video of CAR T cells at work and students will have the option to compose a story about the battles being waged as a cross-curricular connection.  Students can create comic strips or storyboards either with paper and pencil or digitally. This will help them process how the CAR T cells work in the body after we’ve interacted with some of the content. This will be a good formative assessment- we can review and give feedback to make sure learning outcomes are happening as expected.

The immune-oncology field will be a new topic for my students so we will use some vocabulary games/activities, so they become comfortable with the content words.  Some words we will use in these activities might be- antigen, infusion, immunotherapy, receptor, genetically engineered, apheresis, chimeric antigen receptor. Vocabulary activities will include Frayer models, concentration with vocabulary and definition games, a Word Wall in the classroom and making a unit “dictionary” for students who might benefit from a more hands-on reminders of the vocabulary.

We will examine data from case studies discussing how many T cells are harvested from the patients, and how many are reintroduced after the genetic engineering takes place. We can track the initial treatment and hypothesize how many there might be after the CAR T cells reproduce. We will share out how many of the engineered T cells survive after a few years. Other data points that may be interesting to investigate could be comparing the mortality rates before this therapy and after this has become the standard of care.

Students will complete various items from a Choice Board that will show what they have learned. They will have options that would incorporate different learning styles. Examples might include the production of a video or podcast that shares learning, diagrams showing how the CAR T cells attack the blood cancers, a fictional interview with a patient that has undergone this treatment.  Students can pick options that they enjoy, to demonstrate various learning outcomes that will be assigned as the end of unit project.

Learning objectives in the School District of Philadelphia have been aligned with Pennsylvania standards.  We are currently making the move to align with the National standards as put forth by the Next Generation Science Standards. The PA standards that would be appropriate for use in this unit would include PA S8.B.1.14 Identify the levels of organization from cell to organism and describe how specific structures (parts), which underlie larger systems, enable the system to function as a whole. This would govern multicellular organization and the unit question listed in SDP curriculum information that states How are the systems of organisms organized and how do they interact to keep the organism alive? The NGSS standard aligned with this unit would be MS-LD1-3: Use argument supported by evidence for how the body is a system of interacting subsystems composed of groups of cells.

Students will be use Frayer models in order to demonstrate understanding of relevant vocabulary words for this unit.  The teacher will model how to interact with the Frayer models.  This activity will be aligned with Common Core Standard 1.2.8.J that states students will acquire and use accurately grade-appropriate general academic and domain-specific words and phrases; gather vocabulary knowledge when considering a word or phrase important to comprehension expression.  With a Frayer model graphic organizer, the learner indicates the word they are investigating.  The student will then share the definition, as well as facts/characteristics of the term.  Then, examples of the word are shared, and students can illustrate the term or use it in a sentence that will demonstrate that the student has an understanding of the word. Students will compile a set of Frayer models that they can refer back to during the study of this unit.

This unit of study will facilitate students making connections outside the classroom to relevant real-life events and people.  Students will gain “big picture knowledge of CAR T cell therapy and current blood cancer treatment.  They will be able to synthesize their learning and share what they’ve learned in a variety of formats and opportunities.

Classroom Activities

Week 1: Introduction

  • Introduction to content in the unit
  • Watch a YouTube video titled CAR T-Cell Therapy: How Does It Work? at https://www.youtube.com/watch?v=OadAW99s4Ik
  • Connection to mutations previously studied
  • Frayer model activity with content vocabulary (possible entries- antigen, infusion, immunotherapy, genetically engineered, apheresis, chimeric antigen receptor, remission, mutation, differentiate)
  • Students will compose a summary of what they saw from the video (This can be a written assignment, audio or artistic rendering, depending on the learning styles/abilities of the students)

Week 2: Research article

  • Complete more vocabulary words as necessary with Frayer models
  • Read CAR T Cells: Engineering Patients’ Immune Cells to Treat their Cancers using this link for the most recent information gov/about-cancer/treatment/researcher/car-t-cells
  • Students will work with a partner/group and complete a jigsaw summary of the article. (Each team is assigned a section of the article.  During shareout time, each team will share the most important information from their section. This will be recorded on chart paper or a shared Google Doc/Jamboard.  The final product is a cooperative summary everyone can refer back to during the rest of the unit.

Week 3: Case Studies

  • Share the Emily Whitehead story (emilywhiteheadfoundation.org/our-journey/ or https://www.youtube.com/watch?v=pTQuZ2hWa-0 Emily Whitehead First Child Treated in Trial of T Cell Therapy for Acute Lymphoblastic Leukemia are good sources)
  • Share the William Ludwig story (https://www.pennmedicine.org/cancer/about/patient-stories/leukemia-bill)
  • Students will discuss Whitehead and Ludwig’s stories
  • Students will complete the Case Study graphic organizer to organize what they have understood
  • Students will share their abstract with a peer or teacher and get feedback on accuracy and summary points. Complete edits as indicated.

Week 4: Unit Wrap Up

  • Students will decide which mini-projects they would like to complete from the Choice Board
  • Students will have at least two class periods to work on their mini-projects. This could include collaboration time with peers or teachers, as well as editing conferences.
  • On the Choice Board due date, as indicated by the teacher, students will bring in their work to share. Allow time for a gallery walk, feedback time and a reception for students.  (For the gallery walk, students present their work at various stations around the room. Other students walk from station to station and enjoy the work of their classmates.  One option is to leave comment cards for students to leave positive feedback.)

Resources

Materials List for Classroom Use

  • Frayer model graphic organizers
  • Case study graphic organizer
  • Jigsaw article graphic organizer
  • Copy of Choice Board

Reference

  1. Pollack, Andrew (2016) ‘Setting the Body’s ‘Serial Killers’ Loose on Cancer’, New York Times 8/1/2016

Reading List for Teachers

Fesnak AD, et al.  “Engineered T Cells: the Promise and Challenges of Cancer Immunotherapy.” Nature       Reviews. Cancer, U.S. National Library of Medicine, pubmed.ncbi.nlm.nih.gov/27550819/.

Pollack, Andrew. “Setting the Body’s ‘Serial Killers’ Loose on Cancer.” The New York Times, The New York Times, 1 Aug. 2016.

Posey, Avery D., et al.  “A New Model for Defeating Cancer: CAR T Cells.”  Scientific American: 40-43. Print

Viral Attack –T Cells https://askabiologist.asu.edu/t-cell

CAR T Cell and Other Adoptive Cell Therapy Workflows  https://www.thermofisher.com/us/en/home/life-science/cancer-research/immuno-oncology-research/car-t-cell-therapy-research/adoptive-cell-therapy-purification-cell-assays-car-t-cell.html

Antibodies and T Cells Protect against SARS-CoV-2  https://www.nih.gov/news-events/nih-research-matters/antibodies-t-cells-protect-against-sars-cov-2

Emily Whitehead’s Story: CAR T Cell Therapy for Acute Lymphoblastic Leukemia https://www.chop.edu/video/emily-whiteheads-story-t-cell-therapy-acute-lymphoblastic-leukemia

Appendix

PA State ELA Standard- L.8.6 Vocabulary Acquisition and Use- Acquire and use accurately grade-appropriate general academic and domain-specific words and phrases; gather vocabulary knowledge when considering a word or phrase important to comprehension or expression

Common Core Standard 1.2.8.J Acquire and use accurately grade appropriate general academic and domain-specific words and phrases; gather vocabulary knowledge when considering a word or phrase important to comprehension expression

PA State Science Standard- S8.B.1.14 identify the levels of organization from cell to organism and describe how specific structures (parts), which underlie larger systems, enable the system to function as a whole

NGSS Standards- MS-LS1-3: From Molecules to Organisms: Structures and Processes- use argument supported by evidence for how the body is a system of interacting subsystems of groups of cells

LS1.A: Structure and Function- in multicellular organisms, the body is a system of multiple interacting subsystems. These subsystems are groups of cells that work together to form tissues and organs that are specialized for particular body functions.

 Create a comic strip incorporating the CAR T-cell as a hero.

(This can be drawn with paper + pencil or done digitally using Canva or something similar)  

 

Conduct your own research on a cutting edge cancer therapy. Share what you learn in a 2-4 page paper.

 

 

You are a member of a medical team.  You’ve been tasked with creating a letter or video to explain your proposed treatment plan for a patient with Acute Lymphoblastic Leukemia.

 

Summarize the video of the CAR T-cell attacking a cancer cell.

Be sure to use precise, vivid language and description in your writing.

 

A neighbor shares their thinking that all mutations are bad.  Think about what you have learned about mutations in class.

Apply your learning and come up with a response for your neighbor.  Be sure to include beneficial/harmful mutations as examples.

 

Consider what you’ve learned about CAR T-cells as an effective treatment plan for blood cancers.

Develop an ad campaign to promote it.

 

Arrange a T-cell’s journey from a regular immune cell to a super charged CAR T-cell.

This flow chart can be an illustration or a written piece.

 

Share about a highlighted patient from the Emily Whitehead Foundation.  Include their age, condition, prognosis and outcome.

 

Emilyehiteheadfoundation.org/

patientstories

 

Investigate careers that are associated with what we’ve been learning about.  Select one and write about it!

Include the educational requirements, job description, salary as well as your favorite part of the job.

Name___________________________

Patient Case Study

Information Source _________________________________________________

Patient Name ______________________________________________________

Age at Disease onset ________________________________________________

Therapy History  ___________________________________________________

CAR T-cell reaction ________________________________________________

Summary of Patient History and Treatment Outcome: _____________________
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