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Appreciating the Complexity: Immune Escape and Immune-Related Side Effects

by Mark G. Kris, MD


As seen at the 2022 ASCO Annual Meeting, researchers continue to work toward a better understanding of the complexity and sophistication of the immune system. Immune escape and immune-related adverse events (irAEs) were areas of particular clinical interest.

Following the conference, featured expert Mark G. Kris, MD, was interviewed by Conference Reporter Editor-in-Chief Tom Iarocci, MD. Dr Kris presents his clinical perspectives on relevant emerging data here.

Mark G. Kris, MD

Attending Physician, Thoracic Oncology Service
William and Joy Ruane Chair in Thoracic Oncology
Memorial Sloan Kettering Cancer Center*
Professor of Medicine
Weill Cornell Medical College
New York, NY

"There is the concept of hot and cold tumors. Immune escape may be crucial for some tumors to thrive, but the growth and proliferation of other tumors may not depend on the evasion of the immune system."

Mark G. Kris, MD

The immune system is highly efficient and complex, and that is probably why it so often keeps us from dying from infections. This complexity also makes it very difficult to focus on any one particular component when trying to modify immunity to achieve a desired therapeutic result. The analogy that I like to use is that the immune system is like a symphony, where there are dozens of musicians and instruments, with many subtle things going on. Consider an ensemble that includes 30 violins and 7 violas. If this composition is suddenly changed so that 25 violins and 9 violas are now playing, the effect may not be very dramatic or even detectable. However, changing any one instrument might affect the whole symphony on some level, and some instruments have more of an effect than others. 

There is the concept of hot and cold tumors. Immune escape may be crucial for some tumors to thrive, but the growth and proliferation of other tumors may not depend on the evasion of the immune system. Non–small cell lung cancers (NSCLCs) that have co-opted PD-1/PD-L1 and/or CTLA-4 do respond to immune checkpoint inhibitor (ICI) therapy with nivolumab and ipilimumab. This was reported in the update from the CheckMate 227 study by Brahmer et al at the 2022 ASCO Annual Meeting (abstract LBA9025). Although nivolumab and ipilimumab can be very effective in many advanced NSCLCs, this treatment is generally not used in patients with EGFR/ALK-positive NSCLCs because those cancers largely do not rely on immune escape as an important mechanism for initiation and growth. We talk about turning a cold tumor into a hot tumor, but this is not feasible if the cancer cell is driven by other factors.

It is also important to distinguish between patients with cold tumors and patients with tumors that did respond to ICI therapy initially but then their response was lost. One way in which we are trying to counteract suboptimal responses and/or the loss of response is to add a different type of ICI. Various immune-related targets are being investigated, including TIM-3 (abstract 3547), TIGIT (LBA8507), LAG3 (abstract 9003), as well as VEGF (abstract 1070). At the meeting, we saw many effective agents with good pharmacokinetics and solid activity against all of these targets. Of course, when a second drug is added, such as an anti-VEGF agent, we are adding a toxicity and an uncertain degree of benefit. Thus, more data are needed to determine the risk-benefit profile for each of these approaches.

Regarding irAEs, there are several points to emphasize. First, there is a general consensus that having some irAEs signifies the ability of an ICI to activate the immune system, which can be a sign of efficacy. It is often useful to convey to patients that having irAEs may portend a better result in controlling their cancer. 

Additionally, multispecialty care can be extremely valuable in the management of irAEs. Hypophysitis is a serious irAE, but one that becomes very manageable when recognized and dealt with promptly. I would urge oncologists to enlist the help of colleagues in endocrinology to help manage those cases, to be ready for that side effect, and to take care of it promptly, but not to let the fear of hypophysitis dissuade them from using immunotherapy, as many patients with advanced NSCLC have been cured with nivolumab and ipilimumab. 

Finally, we are moving toward the use of specific biologically targeted agents to counteract irAEs to treat them in a most precise way. At many institutions, individual clinicians have become specialized in treating irAEs and can be called upon to help with these cases. This includes using mycophenolate for ICI-induced hepatitis or an anti–tumor necrosis factor agent such as infliximab for colitis and different dermatologic side effects. The field is moving away from reliance on corticosteroids because we achieve better results with the use of biologically targeted agents such as infliximab than we do with corticosteroids—and we avoid the serious AEs of corticosteroids. 


Algaze S, Baca Y, Brodskiy P, et al. Characterization of TIM3 and its ligands in colorectal cancer [abstract 3547]. Abstract presented at: 2022 American Society of Clinical Oncology Annual Meeting; June 3-7, 2022.

Amodio V, Mauri G, Reilly NM, et al. Mechanisms of immune escape and resistance to checkpoint inhibitor therapies in mismatch repair deficient metastatic colorectal cancers. Cancers (Basel). 2021;13(11):2638. doi:10.3390/cancers13112638

Brahmer JR, Lee J-S, Ciuleanu T-E, et al. Five-year survival outcomes with nivolumab (NIVO) plus ipilimumab (IPI) versus chemotherapy (chemo) as first-line (1L) treatment for metastatic non–small cell lung cancer (NSCLC): results from CheckMate 227 [abstract LBA9025]. Abstract presented at: 2022 American Society of Clinical Oncology Annual Meeting; June 3-7, 2022.

Fan L, Liu X, Jin X, et al. The safety, tolerability, and preliminary antitumor activity of sitravatinib plus tislelizumab in patients with locally recurrent or metastatic triple-negative breast cancer [abstract 1070]. Abstract presented at: 2022 American Society of Clinical Oncology Annual Meeting; June 3-7, 2022.

Felip E, Majem M, Doger B, et al. A phase II study (TACTI-002) in first-line metastatic non–small cell lung carcinoma investigating eftilagimod alpha (soluble LAG-3 protein) and pembrolizumab: updated results from a PD-L1 unselected population [abstract 9003]. Abstract presented at: 2022 American Society of Clinical Oncology Annual Meeting; June 3-7, 2022. 

Johnson DB, Nebhan CA, Moslehi JJ, Balko JM. Immune-checkpoint inhibitors: long-term implications of toxicity. Nat Rev Clin Oncol. 2022;19(4):254-267. doi:10.1038/s41571-022-00600-w

Marin-Acevedo JA, Chirila RM, Dronca RS. Immune checkpoint inhibitor toxicities. Mayo Clin Proc. 2019;94(7):1321-1329. doi:10.1016/j.mayocp.2019.03.012

Postow MA, Sidlow R, Hellmann MD. Immune-related adverse events associated with immune checkpoint blockade. N Engl J Med. 2018;378(2):158-168. doi:10.1056/NEJMra1703481 

Raschi E, Mazzarella A, Antonazzo IC, et al. Toxicities with immune checkpoint inhibitors: emerging priorities from disproportionality analysis of the FDA Adverse Event Reporting System. Target Oncol. 2019;14(2):205-221. doi:10.1007/s11523-019-00632-w

Rudin CM, Liu SV, Lu S, et al. SKYSCRAPER-02: primary results of a phase III, randomized, double-blind, placebo-controlled study of atezolizumab (atezo) + carboplatin + etoposide (CE) with or without tiragolumab (tira) in patients (pts) with untreated extensive-stage small cell lung cancer (ES-SCLC) [abstract LBA8507]. Abstract presented at: 2022 American Society of Clinical Oncology Annual Meeting; June 3-7, 2022.

This information is brought to you by Engage Health Media and is not sponsored, endorsed, or accredited by the American Society of Clinical Oncology.

* Dr Kris is acting in his personal capacity as author of this article. 

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