Adapting Cancer Immunotherapy Models for the Real World

Abstract

Early experiments in mice predicted the success of checkpoint blockade immunotherapy in cancer patients. However, these same animal studies failed to accurately predict many of the limitations and toxicities of treatment. One of the likely reasons for this discrepancy is the nearly universal use of young healthy mice, which stand in stark contrast to diverse patient populations varying in age, weight, diet, and hygiene. Because these variables impact immunity and metabolism, they also influence outcomes during immunotherapy and should be incorporated into the study design of preclinical experiments. Here, we discuss recent findings that highlight how efficacy and toxicity of cancer immunotherapy are affected by patient variation, and how distinct host environments can be better modeled in animal studies.

Keywords: age; cancer; checkpoint blockade; immunotherapy; microbiota; obesity.

Figure 1. The challenges of immunotherapy in obese mice

(A) Obesity was induced in BALB/c mice fed high fat chow (60% kcal) for 20 weeks. Renal tumor cells were established in the kidney for 7 days followed by treatment with Ad-TRAIL and CpG. Normal weight mice responded to treatment through activation of DCs and induction of IFNγ⁺ CD8⁺ T cells and arrested tumor growth. Tumors in obese mice receiving the same treatments were infiltrated with regulatory DCs and reduced T cell numbers and progressed rapidly. No toxicity was reported in treated obese mice [13]. (B) In a second study, obesity was induced in C57BL/6 mice either by high fat diet (60% kcal) or genetic ablation of the gene encoding leptin (ob/ob). In young normal weight mice with renal cell tumors, immunotherapy with anti-CD40 and IL-2 provided a long-term survival benefit, reliant on DCs and CD8⁺ T cells [86]. The same immunotherapy in obese mice resulted in rapid and lethal toxicity mediated by TNF produced by elevated numbers of macrophages [14]. Immunotherapy with checkpoint blockade antibodies has not yet been tested in obese mice.

Figure 2. The effects of commensal microbiota on cancer immunotherapy

Distinct commensal microbes are known to have a range of effects on host immunity and tumor progression, and even cancer immunotherapy. Bacteria are grouped here according to their potential influences on cancer immunotherapy, based on published reports. This includes evidence that B. fragilis and Burkholderia combine to protect healthy tissue from therapy-related assault, and that Bifidobacterium and B. fragilis cooperate with checkpoint blockade to promote antitumor immunity. The identification of cooperative and protective genera and species provide an intriguing possibility of probiotic therapy that could be combined with cancer immunotherapy to improve patient outcomes and even convert non-responders.