Immunotherapy Challenges

Although immunotherapy has shown promising results in treatment for different types of cancer there are still many challenges.

The side effect profile of immunotherapy remains challenging for most medical oncologists. The side effects of chemotherapy are well known to us, chemotherapy in general weakens the immune system causing an increased risk of infection. Immunotherapy on the other hand, hyper activates the immune system causing a more peculiar but a variety of toxicity called immune-related adverse events (IRAEs).58 It can vary from mild symptoms such as flu-like symptom, fatigue, body ache to more pronounce involving many organs such as life-threatening pneumonitis, immune-induced colitis, immune-induced hepatitis, hypopituitarism seen in Melanoma and SCLC studies.59,60


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In the IMpassion 130 study of Atezolizumab and Nab-Paclitaxel vs placebo with Nab-Paclitaxel in advanced triple-negative breast cancer, the frequency of nausea cough, neutropenia, pyrexia and hypothyroidism was at least 5 percentage point greater in the Atezolizumab combination arm then the placebo-chemotherapy arm42. The rate of grade 3 or 4 was 48.7%, vs 42.2%. However, fatal adverse events occurred in 6 patients in the Atezolizumab-chemotherapy arm vs 3 patient in the placebo-chemotherapy arm. The 3 deaths in the Atezolizumab paclitaxel group were from autoimmune hepatitis, mucosal inflammation and septic shock. The authors concluded that the unique spectrum of adverse events that are associated with immune checkpoint blockade does necessitate supplementary monitoring and treatment practices beyond those that are required for chemotherapy.

Another challenge remains is the wide variety of atypical clinical response patterns that can be seen across patients with what looks like to be the same type of disease.61–63

Efficacy of immunotherapy varies widely from one patient to the other, even within the same subtype.

This has been well documented in melanoma studies.59,60 Only 15–20% show a complete response while others may have a lesser degree of benefits and even none. Some of those patients who do response have a long-lasting response that can ultimately borderline on cure. It is crucial to be able to predict who would respond, or not respond to therapy, can we alter treatment to obtain a maximal response to immunotherapy?

Also documented data of some patients who respond to therapy after a progression and/or a flare up called pseudoprogression. The pseudo-progression has been reported to be about 4–7% of patients with NSLC treated with PD1 or PD1 inhibitors.64–66 Previously this phenomenon was thought to be the real progression of the tumor. However, it is now known that patients receiving immune checkpoint blockade drugs, the flare up is due to the consequence of treatment-activated immune cells infiltrating the tumor milieu eliciting a radiographic increase in tumor volume, including lesions that were previously not detected in imaging. It is important for the future of immunotherapy that we learn to distinguish between pseudo-progression and actual progression of the disease in order to maximize the effectiveness of treatment. Pseudoprogression has been stated to be around 9% to 29% but not confirmed.66

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As more data emerges from immunotherapy studies in triple-negative breast cancer, we hope to have some of these questions answered and find tools to help us better select our patient for the right therapy. It is rewarding to find new therapies in this patient population, but the focus should also be made to be informed and recognize the many challenges with immunotherapy. The goal should be to select the patients who would benefit the most from immunotherapy based on biomarkers and expression.67

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