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Dr West

How Is Immunotherapy Administered? (An Immunotherapy Primer for Patients, Pt. 2)

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Although the different types of immunotherapy, including vaccines, cytokines, and checkpoint blockade therapies, have many distinct features, they are all administered either into the skin or as intravenous (IV) infusion, despite the convenience and appeal of oral therapies to many people with cancer. Immunotherapies are not administered orally because the gastrointestinal (GI) tract would break down the immunologically active large proteins into small, inactive peptide components. In general, vaccines are administered every few weeks for a period of time through skin injections. Cytokines are administered into the skin or, in some situations, via IV. Immune checkpoint blockade therapies are administered via IV, typically every 2 to 3 weeks. Most IV antibodies can lead to acute immune reactions if given quickly, so they are commonly administered over 45 to 120 minutes at a time.

Because the purpose of these immunotherapies is to stimulate the immune system, it is generally recommended that immunosuppressive therapies such as steroids are not given while a patient is receiving an immunotherapy. While conventional cancer chemotherapy is also potentially immunosuppressive, it is still a matter of debate and controversy whether it is helpful or detrimental to administer agents such as checkpoint blockade therapies concurrent with standard chemotherapy. Clinical trials are seeking to answer this question.

Another issue that remains undefined is the optimal duration of immunotherapy. In some cases, the toxicity profile has limited the duration of these treatments, such as with ipilimumab, where treatment beyond four cycles is not typically feasible. Thus, treatment with this agent is intended to be capped at four treatments administered every 3 weeks. In contrast, many PD-1 and PD-L1 inhibitors are administered on an ongoing basis every 2 or 3 weeks, in the absence of significant progression or prohibitive toxicity. There may, however, be cumulative side effects, not to mention the inconvenience and expense of treatment given continuously for potentially well over a year. Although trials with some cytokines, CTLA-4 inhibitors such as ipilimumab, and also some PD-1 or PD-L1 inhibitors have ended treatment after a fixed duration or when patients have expressed concerns related to side effects, these agents have demonstrated very sustained responses/nonprogression that can be ascribed to the “memory” of the immune system. It remains to be determined whether patients who achieve good responses to some well-tolerated therapies such as PD-1 or PD-L1 inhibitors need to continue receiving these agents indefinitely, even if they can, to achieve the best results possible. It has been exciting to see responses that potentially last years, leading to questions of whether these responses may be indefinite and tantamount to cures for some patients. With benefits that may last for years, it will become important to clarify the required duration of treatment, so that patients are not obliged to receive ongoing, indefinite treatment that may not be truly necessary and may be associated with a greater risk of cumulative side effects, which are discussed here.

Importantly, patients receiving immunotherapies can demonstrate a distinct pattern of response compared with cancer treatments we have used for many years, such as standard chemotherapy and some molecular-targeted therapies. For decades, we have come to expect to see the most dramatic responses to our cancer treatments very early in the course of treatment, with diminished efficacy over time. Immunotherapies often demonstrate a different pattern of stable disease or even the appearance of enlargement of existing areas of disease, followed by delayed tumor shrinkage that may continue over many subsequent scans. This is sometimes visualized in the form of a “spider plot,” in which the tumor burden of a given patient is plotted over time as a line moving from a horizontal level up or down, going from left to right as treatment continues (Figure 2). The unusual pattern of initial enlargement of measurable areas of disease or sometimes even the appearance of new lesions after the start of immunotherapy followed by delayed response is known as pseudoprogression. When biopsied, these lesions actually demonstrate infiltration by lymphocytes, the cells of the immune system that mediate an anticancer immune response, which can precede the shrinkage or eradication of the cancer in that area. Presumably, each apparent new lesion that subsequently resolves represents an area that was a small cancer focus below the level of visibility on scans prior to immunotherapy, which then became newly visible after getting infiltrated with lymphocytes following the initiation of immunotherapy, only to shrink or resolve later.

Responses to immunotherapies may follow a delayed timeline and be preceded by a period of tumor enlargement and/or new lesions appearing. In this “spider plot”, lines from left to right track the change in the overall disease burden of patients on nivolumab, and the rise or fall in the line represents a relative increase or decrease, respectively, in the overall size of measurable “target” lesions on imaging for each patient.  These lines demonstrate the variability of the patterns seen, as well as the potential for prolonged response that may be of delayed onset. 1.	From: Topalian SL et al. J Clin Oncol. 2013;31(suppl: abstract 3002).

Figure 2: Responses to immunotherapies may follow a delayed timeline and be preceded by a period of tumor enlargement and/or new lesions appearing. In this “spider plot”, lines from left to right track the change in the overall disease burden of patients on nivolumab, and the rise or fall in the line represents a relative increase or decrease, respectively, in the overall size of measurable “target” lesions on imaging for each patient. These lines demonstrate the variability of the patterns seen, as well as the potential for prolonged response that may be of delayed onset.
1. From: Topalian SL et al. J Clin Oncol. 2013;31(suppl: abstract 3002).

While delayed responses and pseudoprogression are important possibilities to consider, to avoid discontinuing a potentially effective therapy too early, it is important to recognize that pseudoprogression occurs only in a minority of cases (perhaps 10%). Many experts recommend that, in the face of what appears to be progression on early scans, it is important to evaluate other factors that can help distinguish pseudoprogression from true progression, such as whether a patient is experiencing increasing pain, losing weight, or generally feeling well. In the absence of other signals of deterioration, it is very appropriate for patients to continue on immunotherapy and monitor their clinical response through scans over time. On the other hand, it is also important not to delay an appropriate change in treatment if a patient is experiencing escalating cancer-related symptoms along with ambiguous scan findings, in which case the patient is far more likely to be experiencing true progression rather than pseudoprogression.

This educational summary is intended for patients with cancer, their caregivers, and other interested non-clinicians, and is part of a broader educational platform focused on immuno-oncology, available at www.peerviewpress.com/e158

The Immunotherapy Primer for Patients is a collaboration between GRACE and PVI, PeerView Institute for Medical Education


3 Responses to How Is Immunotherapy Administered? (An Immunotherapy Primer for Patients, Pt. 2)

  • lablady says:

    Dr West,
    As I mentioned before my husband has been offered a spot in Dr Juergens new clinical trial for MED14736. I have watched all the immunotherapy videos which were very well done and informative and would like to ask about a few points.1) After listening to Dr Atkins, it seems to me that my husband is unlikely to be PDL 1 positive since he is a never-smoker. He will be tested but we will not know the results. If you are PDL 1 negative there is a low probability that this therapy will help him. 2) Are the immune- mediated side effects reversible once the therapy is stopped or are they a life long issue for the patient. There was no record of his tumor being tested for EGFR or ALK , should this be done for ?

  • Dr West
    Dr West says:

    I would advise you to review this summary:

    http://cancergrace.org/cancer-treatments/2014/12/30/which-cancers-and-which-patients-an-immunotherapy-primer-for-patients-pt-3/

    The association of PD-L1 expression with response is quite variable and not extremely strong. There are responders who are PD-L1 negative, and the difference in response rate between PD-L1 positive and PD-L1 negative patients is not striking in several studies.

    It is unknown how long a patient needs to be on these immunotherapies. It is possible that treatment for a limited period is just as effective as ongoing treatment, but this is simply not known today.

    Testing for EGFR and ALK is standard of care for newly diagnosed patients with a non-squamous NSCLC.

    Good luck.

    -Dr. West

  • lablady says:

    Dr West. Thanks so much for the info. We have decided to go ahead with the clinical trial. Even if my husband receives the placebo he will for sure get good follow up.

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