What Is Immunotherapy?

Matthew Halpert, PhD

In the late 1800’s Dr. William Coley stumbled onto an interesting observation, that an active immune response in the area of a tumor could delay and even occasionally eliminate a cancerous threat1, 2.  Though he didn’t fully understand the mechanisms at that time, he essentially demonstrated the power of the immune system even against a threat as tough as cancer.  And though these “toxins” were occasionally able to generate a successful response, the underpinnings were still obscure and not practical to mainstream medicine.  This left the door open for simpler paradigms, such as chemotherapy and radiation, to lead the efforts in the fight against cancer3.  Though rife with failure and collateral damage, these remain the leading options even today.

Immunotherapy and the Immune System

Although it took roughly 100 years, utilization of the immune system against cancer began to garner more attention as A) chemotherapies continued to struggle against a variety of diseases and B) the scientific field had gained a better understanding of the cells and mechanisms powering the immune response.  Within the first decade of the 2000s, a couple of pivotal clinical trials in which nothing more than removing a “brake” that turns off an immune response was pharmacologically blocked – raising the survival rate from 0% (with chemo) to about 5-10% in very fatal cancers – reinvigorated the field4, 5.  This may initially seem disappointing and low until one realizes the promise held within such a result.  If a non-specific immune system “booster” could do in 10 years what chemotherapy had been unable to do in 100, then the sky is the limit as we continue to study and understand the true power of our immunity.  The immune system canfight back and win against cancer.  Paradigms shift. 

Types of Immunotherapy: Vaccines, Monoclonal Antibodies, Dendritic Cells, and More

It is important to understand that “immunotherapy” is a broad category encompassing all that angles to educate and empower a patient’s own immune system to destroy cancerous tissue.  There is not one type any more than there is one type of chemotherapy or one type of “medicine.”  Some of the more common types of immunotherapy today include checkpoint inhibitors, CAR-T cells, antibodies, and Dendritic Cell Vaccines

  • Checkpoint inhibitors, such as against “immune breaks” CTLA-4 and PD-1, interfere with a tumor’s ability to dampen an attacking immune response.  By being effectively blocked from pressing the immune cell “off” switch, the immune response can act longer and stronger6, 7.
    • Pros:
      • Easy to administer / Off-the-shelf
      • Applicable to a variety of cancers
      • Relatively safe
      • Can delay tumor progression, potentially reversing and in some cases eliminate
    • Cons:
      • Not personalized to a patient or a patient’s cancer
      • Non-specific in attack; fails to educate the immune system
      • Limited half-life and limited efficacy
      • Cancer is able to evolve to avoid and render useless8, 9
      • The potential for long term toxicity issues10, 11

  • CAR-T cells are a patient’s own T cells that have been genetically modified in the laboratory to “shortcut” the natural immune system and engender a Killer T cell response against a specific marker expressed on the tumor.
    • Pros:
      • Able to target a patient’s Killer T cells against a cancer
      • Is more personalized than checkpoint inhibitors, but less than Dendritic Cell Vaccines
      • Can be self-perpetuating and ongoing
      • Integrates into a natural immune response against hematological malignancies
      • Can delay cancer progression, potentially reversing and in some cases eliminate
    • Cons:
      • Tends to be too weak to overtake solid cancers12, 13
      • Typically, only targets a single antigen expressed14
        • Which can be downregulated, rendering the treatment worthless
        • Which can be expressed on normal cells, leading to off-target destruction
      • Not adaptive; does not follow normal pathway for an immune response
      • Can cause off-target toxicity15, 16
      • Very expensive17, 18

  • Antibodies are drugs that essentially have 2 functional ends, 1 end targets something expressed on the cancer and the other end recruits immune cells to the site in hopes of introducing an immune attack.
  • Pros:
    • Easy to administer / Off-the-shelf
    • Applicable to a variety of cancers
    • Relatively safe
    • Can delay cancer progression, potentially reversing and in some cases eliminate
  • Cons:
    • Generally, does not incite a very strong immune response19, 20
    • Not personalized to a patient or a patient’s cancer21
    • Non-specific in attack; fails to educate the immune system22
    • Limited half-life and limited efficacy
    • Cancer is able to evolve to avoid and render useless23, 24
    • Typically, only targets a single antigen expressed25
      • Which can be downregulated, rendering the treatment worthless
      • Which can be expressed on normal cells, leading to off-target destruction

  • Dendritic Cell Vaccines are the attempt to utilize the natural immune system pathways to generate a global, multi-faceted, and ongoing immune response capable of widespread surveillance and destruction of all cancerous cells.
    • Pros:
      • Applicable to a variety of cancers26, 27
      • Relatively safe28, 29, 30
      • Can delay cancer progression, potentially reversing and in some cases eliminate30, 31, 32, 33
      • Is the most personalized immunotherapy34
      • Can be self-perpetuating and ongoing35, 36, 37
      • Mimics a natural immune response from the “top-down38, 39
      • Leads to the most global immune response40
      • Adaptive; can target multiple antigens expressed on the cancer making it tougher for the cancer to “hide41
      • Can reduce expression of “brakes” on immune cells to overcome immunosuppressive attempts by tumor microenvironments42, 43
      • Most likely immunotherapy to generate immunological memory to help fight against relapses37
    • Cons:
      • Not off-the-shelf; not 1-size fits all
        • An expensive process made for each patient
      • Previous attempts failed to fully activate Dendritic Cells which led to limited activity
      • Depending on protocol, can require a fresh sample of the patient’s tumor
      • Has not demonstrated success against hematological malignancies 
      • Does not delay or reduce tumor burden while immune system ramps up

Immunotherapy In Clinical Trials

Since showing effectiveness in treating cancer, there have been a variety of different clinical trials launched to continue to study the impact that may be possible with immunotherapy. Within the past decade, over 600 trials have been completed for checkpoint inhibitors alone, with another 1800 studies listed as of today, and this is but one immunotherapy modality44.  As successes continue to accumulate across the spectrum, it is expected that this number will grow and eventually overtake chemotherapeutic trials.

Immunotherapy Treatment And Side Effects

As with any treatment, patients have a right to be aware of the potential side effects and what may be expected in general.  Every patient is unique and therefore effects experienced can be different between individuals undergoing the same treatment, but there are a few generally shared traits that can and should be discussed.

To begin, most immunotherapies will share common symptoms of an “immune response” which can include things such as fever, chills, muscle aches, fatigue, swollen lymph nodes, swollen tumors, inflammation, nausea, appetite changes, and the sort45, 46.  Essentially, the therapy is activating or educating a patient’s own immune system to begin destroying the cancer the same way it would destroy an invading pathogen.  And eliminating a pathogen that is beyond the introductory stage usually is accompanied with symptomatic evidence of an immune response.  Are these side effects?  Or rather just the effects of a functioning immune system finally attempting to fight back the cancer?

As a note, within many trials and publications these symptoms may be classified as “Adverse Events (AEs),” which can sometimes scare people who imagine AE’s must refer to things such as 

stroke, paralysis, and death.  AEs are extremely important to track to understand how dangerous a treatment option may be, and until any particular event (a.k.a. symptom) is linked to a positive clinical outcome, it must be considered “Adverse.” But a runny nose can be considered adverse, and this alone should not deter patient’s from exploring these treatment options.

Other than these “natural” symptoms or side effects, the rest of the profile may boil down to the specific type of immunotherapy and to any underlying condition a patient may present with.  For example, immune checkpoint inhibitors tend to boost the entire immune response and not just a response against the cancer.  This can lead to off-target inflammation and truly erroneous outcomes.  However a therapy such as Dendritic Cell Vaccine tends to be far more targeted and specific and thus off-target effects are minimal.  This is not to imply there are no risks at all, but as with any treatment option at this juncture, the benefits must be weighed against the risk potential.

Is Immunotherapy a Legitimate Cancer Treatment? Closing Thoughts

In general, the concept of Immunotherapy is simple: Empowering your own immune system to do what it normally does – protect you from a threat.  And although the overarching principles of such a cancer treatment have been bandied about for over a hundred years, a lack of scientific understanding impeded real progress for much of that time.  However as science has continued to evolve, new treatment options are becoming more mainstream.  In many a sense, immunotherapy has been able to accomplish more in the past ten years for many fatal cancers than chemotherapy has been able to do in a hundred.  The immunotherapy side effect profiles are more biological than toxic (as is the case with non-specific and often barbaric treatments), the chances to avoid relapse are significantly improved with an educated and functional immune system, and many scientists and doctors are -for the first-time- truly believing that cancer can be relegated to nothing more than an annoyance akin to the flu.  There is still much to be done and much to be learned, but it is becoming more and more obvious that we are finally on the right track in our ongoing battle with cancer.  Our own immune system failed in the first place and allowed cancer to grow and take over, so reprogramming our own immune system to correct its own mistake is an ideal and elegant solution with treatment capabilities never previously observed.  The future is fast approaching.

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