Acquired Resistance to Immunotherapy

Future challenges in onco-immunology

Advances in immunotherapy have resulted in significant clinical responses in some patients with cancer. However, one of the biggest challenges in cancer therapeutics is the development of resistant disease and disease progression on or after therapy. Nature Reviews Cancer asked three scientists to give their views on the current evidence for whether acquired resistance to immunotherapy exists in patients and the future challenges posed by immunotherapy. Below we present some of the answers provided by scientists from the US National Cancer Institute, QIMR Berghofer Medical Research Institute in Brisbane, and Memorial Sloan Kettering Cancer Center.

Are there examples of acquired resistance to immunotherapy from clinical trials and model systems, and what are the characteristics of acquired resistance?

Nicholas Restifo: “Before we discuss issues of resistance to immunotherapy, it should be duly noted that immunotherapy is a true paradigm shift in the treatment of patients with metastatic cancer. In terms of lives saved and person-years restored, immunotherapy promises to be more significant than any other form of treatment for patients whose tumours have already metastasized…

… immunotherapy can induce complete and long-lasting tumour regression. Thus, immune-selective pressure for resistant tumour cells must exist, but cause and effect relationships, especially in humans, cannot be drawn with any certainty. Nevertheless, we can theorize about what seems to be happening in our patients, and it is important to distinguish two major categories of acquired resistance of tumour masses to immunotherapy… selection of resistant clones and true acquired homeostatic resistance…”

Mark Smyth: “Several immunotherapies, in particular immune checkpoint-targeting antibodies and adoptive T cell therapies (ACTs), are beginning to transform the treatment of advanced cancers. The likelihood of response to these immunotherapies differs strongly across tumour types, and even in those cancer types that respond … non-responsiveness is observed, indicating the presence of intrinsic resistance or acquired immune resistance. In addition, in a subgroup of patients who do initially respond to immunotherapy, the cancer will later recur, thereby indicating a role of immunotherapy-induced acquired resistance. Intrinsic resistance often occurs in patients with global immunosuppression (for example, patients with HIV and some elderly patients), in tumours that express few molecular cues that can be recognized as foreign to the immune system (for example, non-viral tumours with a low mutational load) or in tumours that display intrinsic resistance to immune-mediated killing mechanisms.

There are many experimental and clinical examples of naturally acquired or immunotherapy-acquired resistance. Multiple inhibitory feedback mechanisms have a role in suppressing T cells in the tumour microenvironment (TME). These comprise the now clinically validated PD1–PDL1 axis and various potentially overlapping immune checkpoint molecules defined by preclinical studies… The general mechanisms of therapy-induced acquired resistance are likely to be very similar to those associated with naturally acquired resistance.”

Alexandra Snyder: “The frequency of acquired resistance to checkpoint blockade immunotherapies has not been systematically documented, although it is well known to clinicians who use such therapies…

The immune-related response criteria (irRC) have been developed to account for the growth patterns unique to immunotherapy-treated patients, specifically to allow for continued treatment on study beyond apparent progression, as some patients experience tumour growth followed by regression. In contrast to RECIST, using irRC, the appearance of new lesions does not automatically indicate progression. In addition, apparent progressive disease must be confirmed 4 weeks after the first immune-related progressive disease (irPD) assessment to qualify as true progression. irRC is often incorporated into immunotherapy trials, although this method does not specifically capture the acquired resistance group…

Clinically, patients who experience acquired resistance to PD1, PDL1 and cytotoxic T lymphocyte-associated antigen 4 (CTLA4) antagonists can be conceived of in two broad categories: those patients who experience systemic disease control indefinitely with outgrowth of one to three discordant lesions, termed oligometastatic progression; and those patients who experience temporary systemic disease control followed by tumour growth at all or most sites. However, the true frequency and possible agent-specific nature of such phenomena have not yet been studied. Anecdotally, acquired resistance to anti-PD1 therapy … seems to occur more often in the second pattern, with fewer cases of isolated discordant lesions such as those that have been described upon treatment with ipilimumab. However, there are exceptions…

It is possible that earlier treatment of patients in the metastatic or adjuvant setting could mitigate the development of discordant or escape lesions; however, the exposure of patients (a subset of whom may be cured) to agents that carry a risk of side effects has limited such studies to date.”

Is there evidence of immunoediting as a mechanism of acquired immunotherapy resistance?

N. Restifo: “… there is substantial evidence for immunosurveillance in humans… The strongest arguments against immunoediting are the powerful, complete and durable responses we observe in the clinic. These responses seem to be the result of T cells recognizing mutated antigens…”

M. Smyth: “Cancer immunoediting is the process by which the immune system controls tumour outgrowth and shapes tumour immunogenicity, and it comprises three phases: elimination, equilibrium and escape.

…natural immunity to human tumours cannot easily be studied functionally in the absence of the genetic tools and controls afforded by animal studies. But advances in next-generation sequencing and epitope prediction now permit the definition of T cell responses against mutant antigens within individual patients, and should now allow the natural immunological history of a patient's tumour to be followed both before and after therapy.”

A. Snyder: “Preclinical data suggest a multitude of potential mechanisms for tumour evasion of checkpoint blockade immunotherapies; to date, immunoediting has not been confirmed in patients treated with checkpoint blockade, although studies of acquired resistance lesions are under way…

Four studies have now illustrated a correlation between elevated mutation burden and response to therapy with anti-CTLA4 or anti-PD1 agents, but these studies evaluate one tumour per patient. These studies also showed that neoantigen burden and mutation burden were correlated, and thus that neoantigen burden is associated with response. However, accurate neoantigen prediction in patients remains a challenge, and requires optimization using a more sophisticated bioinformatic and statistical approach accompanied by in vitro experimentation.”

What do you see as currently the biggest problems facing immunotherapy?

N. Restifo: “…I think there are three problems that deserve to be singled out. It is clear that most successful immunotherapies to date depend on T cells, but the characteristics of highly effective T cells remain largely unknown…The second problem concerns elucidation of the realm of structures that can serve as appropriate target antigens on tumour cells… third major problem facing researchers in the field of immunotherapy: understanding the nature of the target structures recognized by naturally occurring T cells.

As the field moves forward, it seems prudent to offer a more general point about the perils of the statistical analysis of very large data sets. Big data will invariably produce very precise answers, but as the data sets continue to grow the problem of potentially false findings exponentially expands as well. There is no question that high-throughput sequencing has opened vast new horizons. But statisticians since the time of Thomas Bayes have worried about the perils of understanding the world through data. In order to protect ourselves from the traps of big data, we must never forget to take the refuge afforded by cross-validation using independent data sets, especially when the number of parameters available becomes almost inconceivably large.”

M. Smyth: Immunotherapy faces many problems, including those that have been faced by conventional treatments in the past — for example, therapeutic resistance and affordability to all patients — as well as new challenges such as immune-associated adverse events. Rather than being a problem, the greatest challenge immunotherapy faces is rationalizing, while broadening, its utility… Anti-PD1 and anti-PDL1 monoclonal antibodies will likely represent the foundation of many future cancer treatments in type I tumours (defined as PDL1 positive with TILs driving adaptive immune resistance), and immediately the opportunities to combine these agents with surgery, immunogenic chemotherapy and targeted therapy and radiotherapy are obvious. This will account for a good proportion of patients with immunogenic and highly mutated tumours. While an alternative approach using ACT with chimeric antigen receptor (CAR)-engineered T cells brings together elements of treatment relevant to tumours with a TME that lacks T cells, its specificity will need to be paramount. By giving combination therapies to patients earlier, we would expect that up to 50% or more of some cancer types (such as melanoma and renal cell carcinoma) might be effectively controlled for long periods of time.

A large proportion of tumours with an 'immune-ignorant' phenotype (type II; PDL1 negative with no TILs) have a very poor prognosis regardless of any current treatment intervention, and they will require a completely new strategy. This group of patients represents the greatest challenge to immunotherapy and other cancer treatments. It is likely that these tumours will often have strong simple genetic drivers creating no or few neoantigens.”

A. Snyder: “Two of the biggest problems facing checkpoint blockade immunotherapy are scientific and societal. The success of dual therapy with the anti-CTLA4 agent ipilimumab and the anti-PD1 agent nivolumab in patients with metastatic melanoma suggests that combining such agents holds the promise of benefiting a higher proportion of patients with more durable disease control. However, the number of potential rational combinations is dizzying… Furthermore, there are preclinical data to suggest that such agents might also be successfully combined with other therapeutic modalities such as radiation, chemotherapy or CAR-engineered T cell ACT. In addition, the timing of such combinations is likely to be crucial to their efficacy… In the setting of such challenges, the publication of negative data — failed preclinical combinations and dosing schedules — could facilitate the more efficient translation of effective combinations to clinical trials. Finally, although immunotherapy is certainly an important component of cancer therapy, it may not be the universal panacea for all cancers, especially when considered as a single intervention.

The second, societal, issue is intimately tied to the first… The high cost of antibody therapies will weigh heavily on health-care systems that are already overstrained, in part by the cost of cancer care. If the durability of benefit seen with ipilimumab and nivolumab combination in melanoma was also seen in other malignancies, the drug cost might be seen as an 'up-front investment' in the health of patients who would otherwise be sustained on serial lines of chemotherapies that are themselves costly. Setting a higher bar for response could achieve the goal of only advancing towards the approval process those combinations for which the tremendous cost is offset by sustained efficacy in the majority of patients.”

The full article you can read in the ESMO Journals Access programme.


Restifo NP, Smyth MJ, and Snyder A. Acquired resistance to immunotherapy and future challenges. Nature Reviews Cancer 2016; 16: 121–126.