Types of immunotherapy

What are the 9 immunotherapy approaches

1. Vaccine

2. ACT

3. Microbial Therapy (bacteria and virus)

4. Ig, Mabs vs cancer antigens

5. Engineered TCR

6. CAR-T, HIT-T, CAR-NK

7. Gene therapy of cancer cells

8. Checkpoint initiators (Mab)

9. Combo

Explain the difference between preventative and therapeutic vaccines

→Preventative: Given to healthy individuals to build immunity and stop diseases before they start.

→Therapeutic: Given to individuals to boost the body’s natural defenses to fight existing cancer, reduce tumors or prevent recurrence. 

Explain how vaccine immunotherapy works

Vaccines are designed with specific tumor antigens combined with an adjuvant to boost the immune response. Cells are removed from a patient's tumor, modified with synthetic peptides (specific to a tumor) to trigger a highly targeted immune response and then re-injected. When administered, the vaccine teaches T cells to identify these antigens as harmful, initiating an immune attack against the cancer. The T_C cells seek out and destroy tumor cells throughout the body, ideally making memory cells to prevent recurrence.

What are the pros and cons of Vaccine immunotherapy

1. PROS

→Theyre precise and specific, designed to only target celsl with unique markers or antigens.

→Provides long term protection via memory cells, it can recognize and attack target if it reappears.

→It has a reduced risk of recurrence and fewer acute side effects compared to chemotherapy.

2. CONS

→They are personalized to the patient which is expensive

→Cancer cells can learn to evade the immune system by hiding or creating an immunosuppressive environment that prevents vaccine-activated T cells anergic.

Explain how ACT immunotherapy works

It supercharges the immune system, involves collecting a patient's natural immune cells, enhancing them and infusing them back into the patient to hunt down tumors. 

→T cells are extracted either from patients blood or directly from within a surgically removed tumor (known as Tumor-Infiltrating Lymphocytes or TILs). In a lab, the cells are grown in massive numbers & can be genetically altered to spot specific proteins on the surface of cancer cells. Before the cells are returned, the patient undergoes irradiation to create space in the body and removes competing, suppressive immune cells so the new, robust cells can survive. The expanded, highly active cells are returned to the patient via an IV drip to then multiply and launch a targeted attack against the cancer. 

What are the pros and cons of ACT immunotherapy

1. PROS

→Precise: because they're engineered to hunt specific markers and spare healthy tissue better than chemotherapy.

→Long term immunity: Because they’re "living" cells, they can multiply and remain in the body for a long time, providing long-lasting immunity and preventing recurrence.

→Durable: They can induce deep, complete remissions even in patients with late stage cancer. 

2. CONS

→Side effects: The rapid activation of the immune system can cause severe inflammation and Cytokine Release Syndrome (CRS), which requires careful monitoring.

→Expensive and Time consuming: because they're customized for each individual, and the cell-culturing takes weeks/expensive.

→For specific cancer types: While theyre highly effective against blood cancers, it's hard to penetrate and survive in the dense immunosuppressive environments of solid tumors. (except for TCR)

What are the 6 types of ACT immunotherapy?

1. TIL (Tumor-Infiltrating Lymphocytes)

2. CAR-T

3. HIT-T

4. TRUCK-T

5. CAR-NK

6. TCR

Explain TIL (Tumor-Infiltrating Lymphocytes)

Extracts the T cells that are inside the patient’s tumor, grows them in massive numbers and reintroduces them. This is highly effective for metastatic melanoma.

what are the pros and cons of TIL immunotherapy

1. PROS

→Highly effective in solid tumors and are naturally able to attack tumor-specific antigens without requiring genetic engineering.

→Can lead to durable, long-term remission and designed as a single infusion treatment

2. CONS

→Expensive as it take weeks to harvest T cells and sometimes not enough TILs available to create the treatment

→It requires intensive conditioning chemotherapy and IL-2, causing severe side effects.

→Requires surgery to remove a tumor for cell extraction

Explain CAR-T (ACT immunotherapy type)

Genetically engineers the patient’s T cells to add a special synthetic receptor (CAR). Allowing the T cells to lock onto specific cancer antigens, bypassing the normal rules of the immune system. It’s widely used for blood cancers like leukemia and lymphoma.

→Targeting is highly specific. It has slow availability because they’re personalized and are high risk to CRS and toxicity. They have limited efficacy to solid tumors. T

what are the pros and cons of CAR-T immunotherapy

Pros (Advantages)

• High Efficacy: It offers a potent, sometimes curative, option for aggressive blood cancers (leukemia, lymphoma, myeloma) that have relapsed or failed to respond to traditional therapies.

• Durable Remission: The CAR-T cells can continue to multiply and persist in the body, providing lasting anticancer results and long-term remission for many patients.

• Personalized Treatment: The therapy uses the patient's own immune system, tailored to target specific antigens on their tumor cells.

• One-Time Treatment: Unlike daily chemotherapy or ongoing immunotherapy, it is generally administered once. [1, 2, 3, 4, 5]

Cons (Disadvantages and Risks)

• Severe Side Effects:

  • Cytokine Release Syndrome (CRS): A severe immune response causing high fevers, hypotension, and organ damage.

  • Neurological Toxicity: Known as ICANS, this can cause confusion, seizures, and speech impairment.

  • Infections & Hematologic Issues: Weakened immune systems and low blood cell counts (anemia, thrombocytopenia) are common.

• Limited Efficacy in Solid Tumors: Currently, CAR-T is mostly effective for blood cancers, with limited success in solid tumors (e.g., lung, breast).

• High Costs and Logistics: The process is very expensive and takes several weeks, which may be too slow for patients needing immediate treatment.

• Tumor Antigen Escape: Cancer cells can evolve to lose the antigen that CAR-T cells target, resulting in disease relapse.

• Rare Risk of New Cancers: There is a rare, small risk of developing a second T-cell cancer caused by the therapy.

Explain HIT-T (ACT immunotherapy type)

It bypasses the need for HLA presentation, increasing the sensitivity of engineered T cells to target cancer cells with low antigen levels that typically evades CAR-T therapy. The antigen-recognizing portions of an antibody is directly fused to the constant regions of the T cell’s TCR. Using CRISPR, the genetic code for this new HIT receptor is inserted directly into a highly specific region of the T cell’s genome, ensuring precise engineering while preventing the T cells from attacking healthy tissues. 

what are the pros and cons of HIT-T immunotherapy

1. PROS

→They are extremely sensitive, and act faster, meaning they don’t need to latch onto the cancer cell for very long.

→They’re MHC independent, working independently of HLA/MHC molecules, overcoming a common tumor evasion tactic where cancer cells hide their MHC markers.

→By wiping out low antigen cancer cells, it shows great promise in preventing relapse. 

2. Cons

→Theyre expensive to make and may target normal tissue expressing the same antigen at low levels, requires lengthy research.

→Has risk of cytokine release syndrome (CRS)

Explain TRUCK-T (ACT immunotherapy type)

The 4th generation of CAR-T cells, they’re engineered with the standard CAR construct but are further modified to produce and secrete cytokines like IL-2. As they attack the tumor, they release these cytokines, creating an inflamed, pro-inflammatory tumor microenvironment. This helps recruit the patient's own natural immune cells to the tumor site. Best for overcoming hard-to-penetrate solid tumors.

what are the pros and cons of TRUCK-T immunotherapy

1. Pros

→Designed for the hostile, immunosuppressive tumor microenvironment (TME) of solid tumors.

→Designed with inducible, switchable systems. The cytokine release is localized only within the tumor microenvironment, reducing systemic toxicities compared to systemic cytokine therapy.

→Once activated, they release cytokines (like IL-12) that act as "cargo," attracting and activating innate immune cells to eliminate tumor cells

→They produce a 3rd signal of cytokines, maintaining the T cell response and preventing early exhaustion.

2. Cons

→More complicated to manufacture bc it must include the CAR construct and the machinery for inducible cytokine production.

→May damage healthy tissue that express the antigen at low amounts.

→The inducible system may lead to variable expression levels of the cytokine cargo between patients.

Explain CAR-NK (ACT immunotherapy type)

Cell source comes from donor/cell lines (allogenic) and targeting is specific + innate. It has fast availability and potential for off-the-shelf and has lowest risk to CRS and toxicity. They have emerging efficacy to solid tumors. NK cells are engineered with CARs to enhance their natural ability to destroy cancer cells.

what are the pros and cons of CAK-NK immunotherapy

1. Pros

→Dont require HLA compatibility so has off-the-shelf potential for immediate treatment and cheaper.

→Cant cause GVHD and has low CRS risk, thus safer.

→Effective in hematological cancers and have potential for better solid penetration due to NKs natural capabilities. 

2. Cons

→NK cells have a short life span which can limit long-term remission and hard to expand in numbers compared to T cells.

Explain TCR (ACT immunotherapy type)

It genetically modifies a patient’s T cells to express specialized TCRs. These altered cells are then grown and infused back into the body to actively hunt and destroy cancer cells with high precision.

->How it works: The patient’s T cells are harvested and then modified via CRISPR to express a newly identified, cancer-targeting TCR. The engineered T cells are multiplied in the lab and are infused back into the patient to circulate and eradicate tumors.

What are the pros and cons of Engineered TCR immunotherapy

1. PROS

→Can recognize markers hidden inside the cell by detecting antigens brought to the surface by the cell’s HLA system.

→Can target solid tumors.  

2. CONS

→TCRs are HLA dependent. HLA patterns vary from person to person, both the patient’s cancer marker and their unique HLA type must match the engineered TCR for the treatment to work.

→TCRs are highly sensitive, so researchers must ensure the engineered receptors do not cross-react with healthy tissues to prevent severe autoimmune-like side effects (known as "on-target, off-tumor" toxicity).

Explain how microbial therapy immunotherapy works

It uses bacteria & viruses to stimulate the immune system, making it better at identifying and destroying cancer cells. It naturally boosts immune responses, acting as a vaccine adjuvant, or using bioengineered microbes to deliver targeted anti-cancer treatments directly into tumors. 

->The microbiome modulation: The microbiome heavily influences how well your immune system responds to cancer treatments like Immune Checkpoint Inhibitors (ICIs). Can do fecal microbiota transplantation (FMT), a process where you take stool from a healthy donor who responded well to immunotherapy and transfer it to a patient who has not responded to help reprogram the patient's gut to boost their immune cells. Can also provide patient with specific beneficial bacteria to promote a gut environment that naturally supports cancer fighting T cells.

Explain the bacterial mediated therapy in microbial therapy

Attenuated bacteria have a natural ability to target tumors, as tumors are low in oxygen and act as a safe haven for bacteria to thrive. Bacteria are highly immunogenic, when they colonize a tumor they trigger the immune system's innate alarm system, drawing  macrophages and T cells to the site.

→BCG is an FDA approved treatment for bladder cancer, while in the 19th century “Coley’s toxins” involved injecting dead bacteria into tumors to stimulate the immune system. 

Explain the Bioengineered & Synthetic Bacteria in microbial therapy

Scientists modify harmless bacteria to become living drugs. These engineered bacteria travel to and colonize the tumor, then release therapeutic payloads (like cytokines) directly into the cancer microenvironment. These synthetic bacteria can be designed with "logic gates", where they only release their anti-cancer drugs when they detect specific tumor signals (low oxygen) or when triggered by an external signal. 

What are the pros and cons of microbial therapy

1. PROS

→Overcomes one of cancer’s biggest problems, the "immunosuppressive TME", which hides cancer cells from the body's natural defenses.

→Restores gut health by Fecal Microbiota Transplants (FMT) and probiotics reintroduce healthy microbes.

→Modules the immune system, calms chronic inflammation and support immune system development.

2. CONS

→Risk of infection in immunocompromised patients

→Bc immune system naturally guards against foreign invaders, microbes struggle to permanently colonize the body

Explain how Ig immunotherapy works

It uses concentrated, donated antibodies (mainly IgG) to treat individuals with weakened immune systems or overactive inflammatory responses. Depending on the condition, it works by either supplementing missing antibodies to fight infections or calming a misfiring immune system to reduce inflammation. 

->How it works: Ig are extracted and purified from the blood plasma of healthy donors, ensuring a broad mix of antibodies that can target a wide variety of pathogens. It operates by 2 mechanisms. The first is replacement therapy for immunodeficient patients that can't produce enough antibodies, the donated antibodies provide immediate passive immunity, neutralizing microbes to prevent recurrent infections. The second is immunomodulation for autoimmune & neurological diseases, high doses of Ig act to reset an overactive immune system. They neutralize harmful autoantibodies, block inflammatory receptors & suppress the excessive production of inflammatory cytokines

What are the pros and cons of Ig immunotherapy

1. PROS

→It replenishes missing antibodies, allowing the body to fight infections effectively.

→It helps calm an overactive immune system, preventing it from destroying healthy tissues

→Has multiple administration methods and improves quality of life by reducing frequency/severity of infecitons

2. CONS

→Side effects: Common side effects during or shortly after the infusion. And has a rare risk of thrombosis.

→Treatment is expensive and requires consistent treatments that take hours.

Explain how gene therapy immunotherapy works

It genetically modifies immune cells or cancer cells to enhance the body's natural defense against tumor cells.

→Key approaches:

1. ACT: therapy TRUCK-T, HIT-T, etc…

2. Microbial therapy: Genetically modified viruses used to specifically infect and multiply within cancer cells, causing them to burst and cause a systemic response.

Explain how checkpoint initiator (CI) immunotherapy works

→How immune checkpoints work: The immune system relies on T cells to recognize threats, thus to prevent the immune system from becoming overactive and attacking healthy tissues, T cells have built-in "off switches" or checkpoints. Therefore, the cancer cells will produce specific proteins on their surface that latch onto the checkpoints of T cells, sending an “off” signal. This successfully turns off the  immune response and hides the cancer from destruction.

→The role of inhibitor drugs: The checkpoint inhibitors are laboratory-made antibodies that block the interaction between the cancer's proteins and the T cell's checkpoints. By blocking the cancer’s false “off” signals, the drugs release the brakes on the immune system, allowing T cells to recognize and kill the cancer cells.

Explain the 2 common drugs that target checkpoints in CI therapy?

→Opdivo and Keytruda: They can block either PD-1 (checkpoint protein on T cell) or PD-L1 (protein on tumor cells) to prevent cancer cells from making the T cells anergic.

→Yervoy: It blocks the CTLA-4 protein, which acts as an “off switch”, to allow T cells to stay active.

What are the pros and cons of checkpoint initiator immunotherapy

1. PROS

→It enhances the body’s natural T-cell response specifically against tumor cells by blocking inhibitory pathways

→Its effective across multiple cancer types.

2. CONS

→Its expensive and cause cause sometimes fatal side effects bc the immune ystem is hyper-activated. it can attack healthy tissue, leading to inflammation in major organs.

→Its often combined with other treatments, as sometimes the drug alone will not be effective.

→Tumors can develop resistance to inhibitors, making treatment ineffective overtime.

Explain how combination immunotherapy works

It’s a cancer treatment strategy that pairs two or more therapeutic agents (like checkpoint initiators, chemotherapy, or radiation) to enhance the immune system’s ability to destroy cancer cells, overcoming resistance seen with single-agent therapies. By targeting multiple, complementary pathways, this approach aims to increase response rates, extend survival, and improve long-term outcomes in patients.

What are the pros and cons of combo immunotherapy

1. PROS

→Combining treatments can lead to improved outcomes and better survival rates for patients with advanced cancers.

→By targeting multiple, distinct mechanisms of tumor immunity, it reduces the probability of cancer developing resistance to treatment.

→Certain combinations can increase the ability of T-cells to enter tumor environments.

2. CONS

→Can lead to severe immune-related effects and is expensive to make.

→Doesnt work on all patients and requires a lot of study to figure out what combinations can work best, not a rapid fix.

Provide 4 ways combination immunotherapy can be used

1. Complementary mechanisms: Combining checkpoint inhibitors tackles different immune-suppressive checkpoints simultaneously, boosting T-cell activation more effectively than a single agent.

2. Pairing with chemotherapy: Combining immunotherapy with chemotherapy or radiation can improve results.

3. Overcoming Resistance: By targeting the tumor microenvironment to break down immunosuppressive factors, these combinations help treat patients who dont respond to immunotherapy alone.

4. Combining immunotherapies: Therapeutic vaccines are often used with checkpoint inhibitors to overcome the cancer’s immune evasion mechanisms.

Explain Graft-versus-host disease (GvHD)

Its a serious complication of allogeneic stem cell transplants where donor immune cells (the graft) attack the recipient's body. 

What is the difference between engineered TCR and ACT immunotherapy

→ACT: Example like CAR-T uses T cells with CAR receptor to recognize and bind to the cell surface tumor antigens independently of HLA, which is ideal for blood cancers.

→Engineered TCR: Its a type of ACT that uses modified α and β chains designed to have a high affinity to recognize tumor-specific peptide antigens. It can target intracellular tumor antigens, and can treat solid tumors.

Which of the 9 immunotherapies are personalized?

1. Vaccine

2. ACT

3. Microbial Therapy (bacteria and virus)

4. Ig, Mabs vs cancer antigens

5. Engineered TCR

6. CAR-T, HIT-T, CAR-NK

7. Gene therapy of cancer cells

8. Checkpoint initiators (Mab)

9. Combo

1. Vaccine

2. ACT

3. Engineered TCR

4. CAR-T, HIT-T, CAR-NK

5. Gene therapy of cancer cells

Which of the 9 immunotherapies are off-the-shelf?

1. Microbial Therapy

2. Ig

3. Checkpoint initiators

4. Combination