Late administration of murine CTLA-4 blockade prolongs CD8-mediated anti-tumor effects following stimulatory cancer immunotherapy

Abstract

We have demonstrated that immunostimulatory therapies such as interleukin-2 (IL-2) and anti-CD40 (αCD40) can be combined to deliver synergistic anti-tumor effects. While this strategy has shown success, efficacy varies depending on a number of factors including tumor type and severe toxicities can be seen. We sought to determine whether blockade of negative regulators such as cytotoxic T lymphocyte antigen-4 (CTLA-4) could simultaneously prolong CD8+ T cell responses and augment T cell anti-tumor effects. We devised a regimen in which anti-CTLA-4 was administered late so as to delay contraction and minimize toxicities. This late administration both enhanced and prolonged CD8 T cell activation without the need for additional IL-2. The quality of the T cell response was improved with increased frequency of effector/effector memory phenotype cells along with improved lytic ability and bystander expansion. This enhanced CD8 response translated to improved anti-tumor responses both at the primary and metastatic sites. Importantly, toxicities were not exacerbated with combination. This study provides a platform for rational design of immunotherapy combinations to maximize anti-tumor immunity while minimizing toxicities.

The yin and yang of co-inhibitory receptors: toward anti-tumor immunity without autoimmunity

“…-Global knockout: lethal autoimmunity 67,68 -Deletion in adult mice: non-lethal autoimmune disease 69 -In vivo blockade: autoimmune disease exacerbation in multiple murine models (diabetes, EAE, etc.) 71,72 -Human disease association: multiple including T1D, autoimmune thyroid disease, and rheumatoid arthritis [267][268][269] -Inducible knockout: No effect on tumor growth 73 -Conditional deletion in Tregs: Reduced transplantable tumor growth 9 -In vivo blockade: Tumor control and/or regression in murine tumor models 66,154,155,224 -First FDA-approved checkpoint blockade therapy for metastatic melanoma 213 PD-1 (programmed death-1) -Global knockout: Severe autoimmune disease. Phenotype depends on mouse strain: BALB/c lethal dilated cardiomyopathy, C57BL/6 mice lupus-like autoimmune disease, NOD mice exacerbated diabetes 81-83 -In vivo blockade: Accelerated and more severe EAE 84 -Human disease association: Multiple including SLE, T1D, ankylosing spondylitis, and rheumatoid arthritis [85][86][87][88] -Global knockout, in vivo blockade or conditional deletion of PD-1 in T cells lead to accelerated tumor clearance in multiple murine cancer models [168][169][170][171] Co-inhibitory receptors on T cells in anti-tumor immunity: a focus on CTLA-4, PD-1, TIM-3, TIGIT and LAG-3 Promptly after their discovery, investigations aiming to target coinhibitory receptors arose and established a new paradigm in therapies for cancer.…”

“…221 Multiple investigations of optimized therapies (combination with other therapies, treatment kinetics, specificity, various Igisotypes or Fc-engineered antibodies) aim to improve the efficacy while mitigating the toxicity of anti-PD1 and anti-CTLA-4 antibodies. [222][223][224] Interestingly, a recent study showed that in combination with vaccines against tumor-associated antigens, the timing of anti-PD-1 blockade influences therapeutic outcome. Particularly, PD-1 blockade under suboptimal priming conditions leads to the emergence of a subset of dysfunctional CD8 + T cells that prevent antitumor immunity.…”

Timing of PD-1 Blockade Is Critical to Effective Combination Immunotherapy with Anti-OX40

“…However, the designs of these types of studies are often empirical and take a straightforward additive approach that may not be optimal considering the unique immunological mechanisms that influence combination treatments. While others have demonstrated that administering checkpoint blockade “late” or for a longer duration than costimulatory antibodies is beneficial with preclinical combination immunotherapies (41,42), to our knowledge ours is the first report to directly compare concurrent combination treatment with non-overlapping, sequential treatment with the same agents. Given that a substantial portion of patients does not respond to PD-1 blockade (in monotherapy or in combination) (1,3), our findings in anti-PD-1 refractory model systems suggest that the use of costimulatory stimulation may impact these patients.…”

Effective Combination of Innate and Adaptive Immunotherapeutic Approaches in a Mouse Melanoma Model

“…Enhanced antitumor effects of checkpoint blockade and local treatment with CpG have been reported (44, 45). A combinatorial therapy using anti-CTLA-4 and agonistic anti-CD40 induced a stronger T cell-mediated antitumor effect than either treatment given individually (46, 47). Anti-CTLA-4 was synergistic with the immunocytokine L19-IL2 (34).…”