Review

Neoadjuvant checkpoint blockade for cancer immunotherapy

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Science  31 Jan 2020:
Vol. 367, Issue 6477, eaax0182
DOI: 10.1126/science.aax0182

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Presurgical immune checkpoint blockade

Checkpoint blockade immunotherapy using antibodies that inhibit the programmed cell death 1 (PD-1) or cytotoxic T lymphocyte–associated protein 4 (CTLA-4) pathways has resulted in unprecedented clinical outcomes for certain cancers such as melanoma. Topalian et al. review advances in neoadjuvant (presurgical) immunotherapy as an important next step for enhancing the response of early-stage tumors to immune checkpoint blockade. They highlight the mechanistic rationale for neoadjuvant immunotherapy and recent neoadjuvant clinical trials based on anti–PD-1 or anti–PD-1 ligand 1 (anti–PD-L1) therapy. Pathological assessment criteria that may provide early on-treatment biomarkers to predict patient response are also discussed.

Science, this issue p. eaax0182

Structured Abstract

BACKGROUND

Immunotherapies that target the interaction of programmed death 1 (PD-1) with its ligands, PD-L1 and PD-L2, have ushered in the modern oncology era. The PD-1 pathway is a key mediator of local immunosuppression in the tumor microenvironment (TME) but can also modulate T cell priming against tumor antigens in secondary lymphoid tissues. In advanced inoperable cancers refractory to other treatments, drugs that block the PD-1 receptor on lymphocytes or the PD-L1 ligand on tumor and/or immune cells [anti–PD-(L)1] can mediate tumor regression. Although anti–PD-(L)1 treatment is broadly active and is regarded as a “common denominator” for cancer therapy, many tumors demonstrate de novo or acquired resistance. Using anti–PD-(L)1 therapies in the neoadjuvant (presurgical) setting, when the tumor is potentially “resectable for cure,” presents a potential solution. There is ample oncologic precedent for this approach with presurgical chemotherapies in breast and lung cancer, associating pathologic response with improved long-term clinical outcomes. Our Review focuses on the development of neoadjuvant immunotherapies in the era of PD-1 pathway blockade, highlighting particular considerations for immunological mechanisms, clinical development, and pathologic response assessments.

ADVANCES

The immunologic effects of the PD-1 pathway on T cell priming, effector function, and exhaustion suggest distinct mechanisms underlying neoadjuvant immunotherapy versus chemotherapy. Whereas neoadjuvant chemotherapy can “debulk” tumors preoperatively, neoadjuvant immunotherapy aims to enhance systemic immunity against tumor antigens, eliminating micrometastatic tumor deposits that would otherwise be the source of postsurgical relapse. Furthermore, neoadjuvant PD-(L)1 blockade while the primary tumor is in place, as opposed to adjuvant therapy directed only against micrometastatic disease after resection, leverages higher levels of endogenous tumor antigen present in the primary tumor to enhance T cell priming.

We discuss scientific evidence that supports two different but not mutually exclusive models by which neoadjuvant PD-(L)1 blockade may promote systemic antitumor immunity. First, anti–PD-(L)1 rejuvenates tumor-specific cytotoxic T cells that already reside in the TME, causing their activation, proliferation, and trafficking to micrometastatic deposits. Second, tumor-draining lymph nodes (TDLN) appear to be the focal point for anti–PD-(L)1 activity, where dendritic cell presentation of tumor antigens to T cells is enhanced; these tumor-specific T cells then enter the bloodstream and migrate to tumor sites. The destruction of micrometastases is central to the notion that neoadjuvant PD-1 blockade should result in enhanced relapse-free and overall survival in operable patients who would otherwise relapse after surgery alone.

There is a strong rationale for evaluating neoadjuvant immunotherapy across tumor types. Presurgical drug administration provides abundant on-therapy tissue for in-depth mechanistic and biomarker studies. We discuss data from recent clinical trials of neoadjuvant anti–PD-(L)1 that show that pathologic tumor regression can outpace radiographic regression and demonstrate the involvement of diverse cellular subsets in this process.

OUTLOOK

At present, more than 100 clinical trials of neoadjuvant anti–PD-(L)1 blockade, as monotherapy or combination therapy, are ongoing or planned. Combining anti–PD-1 with anti–CTLA-4 (cytotoxic T lymphocyte–associated protein 4), or with multidrug chemotherapies for triple-negative breast and lung cancer, has yielded substantial pathologic response rates that are encouraging but require longer follow-up. Next-generation trials may help assign patients to postsurgical observation or intervention depending on the degree of pathologic response, similar to the precedent established with nonimmunologic neoadjuvant therapies in breast cancer. Tumors resected after neoadjuvant immunotherapy provide sufficient materials for in-depth scientific interrogations that are expected to further illuminate mechanisms of response and resistance, revealing pathways and molecules that can be cotargeted in new treatment combinations to increase the efficacy of anti–PD-(L)1 therapy.

Two potential mechanisms for the enhancement of systemic antitumor T cell immunity after neoadjuvant PD-(L)1 blockade.

PD-(L)1 blockade could result in the “in situ” expansion of tumor-specific T cell clones already within the tumor microenvironment. This expansion and activation is largely driven by PD-L1– and PD-L2–expressing dendritic cells in the tumor. Tumor-specific tumor-infiltrating lymphocytes may represent naïve T cells or T cells that have already been “primed” to tumor antigen before PD-1 pathway blockade. In addition, tumor antigen–containing dendritic cells that originate in the tumor pick up tumor antigens and traffic to the tumor-draining lymph nodes, where they present antigens either ineffectively or in a tolerogenic fashion to tumor-specific T cells. PD-(L)1 blockade could act at this point, enhancing productive stimulation of tumor-specific T cells or partially reversing tolerance induction. Activated T cells enter the circulation by way of efferent lymphatics and then egress into tissues.

A. KITTERMAN/SCIENCE

Abstract

Cancer immunotherapies that target the programmed cell death 1 (PD-1):programmed death-ligand 1 (PD-L1) immune checkpoint pathway have ushered in the modern oncology era. Drugs that block PD-1 or PD-L1 facilitate endogenous antitumor immunity and, because of their broad activity spectrum, have been regarded as a common denominator for cancer therapy. Nevertheless, many advanced tumors demonstrate de novo or acquired treatment resistance, and ongoing research efforts are focused on improving patient outcomes. Using anti–PD-1 or anti–PD-L1 treatment against earlier stages of cancer is hypothesized to be one such solution. This Review focuses on the development of neoadjuvant (presurgical) immunotherapy in the era of PD-1 pathway blockade, highlighting particular considerations for biological mechanisms, clinical trial design, and pathologic response assessments. Findings from neoadjuvant immunotherapy studies may reveal pathways, mechanisms, and molecules that can be cotargeted in new treatment combinations to increase anti–PD-1 and anti–PD-L1 efficacy.

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