Clinical efficacy, predictive biomarkers and response patterns of immunotherapy combinations for patients with cancer

The evolving comprehension of cancer immunology has shaped the development of multiple immunotherapy agents that have been implemented in the oncological practice in the past decade. Previous attempts to activate the immune system against cancer cells resulted in low efficacy rates, including treatment with high dose IL-2 and interferon-α. Since the discovery of immune checkpoints like the CTLA-4 and PD-1 and its ligand PD-L1, antibodies that mediate immune-checkpoint blockade have shown improved survival in a subset of patients across multiple cancer types [1,2]. The efficacy of anti PD-1/PD-L1 as single-agent treatments in melanoma, lung cancer, renal cell carcinoma, bladder cancer and others have fueled the development of therapeutic combinations involving other immune checkpoint inhibitors (ICIs), chemotherapy, kinase inhibitors and antiangiogenic agents. In addition, clinical and preclinical research portraying the synergistic effect of other immune-stimulating therapies like cancer vaccines, DNA damage repair inhibition and radiation therapy have renewed immense interest in clinical trial development [3,4].

Immunotherapy combinations for the treatment of patients with solid tumors & response assessment

Standard treatment combinations of ICIs alone or with chemotherapy, antiangiogenic agents and targeted therapies

The combination of monoclonal antibodies directed against different immune checkpoints like anti-PD-1 and anti-CTLA-4 antibodies have proven clinical activity and are now standard treatment options for patients with advanced melanoma, kidney cancer, non-small-cell lung cancer and mismatch repair-deficient colorectal cancers [5–9]. These combinations can mediate effective anti-tumor immune responses by enhancing both the priming of antigen presenting cells (CTLA-4) with T-cells and the activation of effector cytotoxic T-cell-mediated cancer cell death by inhibiting the PD-1/PD-L1 axis. In addition, other ICI combinations are currently in development, aiming to prolong patients survival in the advanced setting and improve cure rates in early-stage disease.

Chemotherapy in combination with anti PD-1/PD-L1 ICIs prolongs survival in patients with metastatic non-small-cell lung cancer, small-cell lung cancer, head and neck and triple-negative breast cancer compared with chemotherapy alone, becoming the new standard treatment in selected patients for which chemotherapy was historically the sole treatment option [10–14]. Some of the mechanisms in which chemotherapy can favor immune responses include immunogenic cancer cell death and tumor neoantigen presentation. Together with chemotherapy, the combination of antiangiogenic agents with anti PD-1/PD-L1 antibodies also prolongs disease control and impacts survival outcomes in patients with cancers in which angiogenic modulation is a key target like metastatic renal cancer and hepatocellular carcinoma [7,8,15]. In this special edition, Bluthgen et al. [16] review the current standard indications of immune checkpoint combinations. In the near future, ICI combinations will expand to include a varied repertoire of new drugs that can enhance and modulate immune responses against cancer cells.

Combination treatments with immunotherapy in patients with brain metastases

The treatment of patients with metastatic cancer involving the brain is challenging due to the morbidity caused by neurologic deficits, seizures and intracranial hypertension [17]. Patients with symptomatic or untreated brain metastasis and patients who required systemic corticosteroid administration were excluded from most clinical trials assessing the activity of immune checkpoint combinations. The unique features of the CNS microenvironment and the genomic clonal evolution of brain metastasis may convey differential responses to immunotherapy between intracranial and systemic metastasis [18]. Henon et al. [19] review the current clinical evidence for combination of ICIs alone, with chemotherapy or antiangiogenic agents, in the setting of brain metastasis. Although current evidence is limited, ongoing studies are exploring the role of immunotherapy combination regimens in patients with untreated brain metastasis from melanoma, renal cell carcinoma and lung cancer.

Clinical consideration for choosing combination therapies in special populations

In addition to patients with untreated brain metastasis, elderly patients or individuals with poor performance status, or requiring corticosteroids, have been excluded or underrepresented in clinical trials with ICI combinations. De Giglio et al. [20] review the current clinical evidence regarding treatment with immunotherapy combinations of patients with non-small-cell lung cancer and clinical features of poor prognosis.

Atypical patterns of response & progression in the era of immunotherapy combinations

The widespread use of ICIs in the treatment of most cancer types has defied the traditional evaluation of response and progression patterns that were designed to evaluate chemotherapy or kinase inhibitor outcomes [21]. The phenomenon of pseudoprogression with immunotherapy, defined as the transient enlargement of tumor metastasis and the appearance of new lesions that later remit, initially confounded clinicians and practitioners [22]. In addition, novel patterns of disease progression with immunotherapy have been described, including hyperprogressive disease, fast progression and early death with immunotherapy agents and has opened a window for extensive molecular and immunological characterization to predict the onset of such poor clinical outcomes [23]. In this edition, Ferrara and Matos review the different atypical patterns of response to immunotherapy and molecular features associated with these patterns [24].

Targeting DNA damage response & repair genes to enhance anticancer immunotherapy

DNA damage repair pathways are key determinants of DNA integrity in the setting of carcinogenic events. Genomic alterations that impair effective DNA repair are frequently found in several cancer types like BRCA1/2 deleterious mutations in ovarian carcinomas and defects in mismatch repair genes like in colorectal cancer. Tumors with defective homologous recombination DNA repair secondary to BRCA1/2 alterations are highly sensitive to PARP inhibitors due to synthetic lethality, leading to the development of these drugs in ovarian, breast, prostate and pancreatic cancers. Defects in the DNA repair network may also have implications in immune-mediated cancer cell death through a variety of mechanisms [25]. Impaired DNA repair can lead to the accumulation of DNA mutations (and higher tumor-mutational burden) that can later be transduced into aminoacidic changes in proteins that are presented as mutant peptides (tumor neoantigen dependent) through the major histocompatibility complex and trigger immune responses [26,27]. In addition, damaged DNA can be released from the nucleus to the cytosol and be detected by the cGAS STING pathway that results in the expression of interferon gamma response genes that include expression of the checkpoint inhibitor PD-L1 [28]. Preclinical studies with in vitro models have shown that targeting DNA damage response (DDR) can induce PD-L1 expression and enhance the activity of anti PD-1/PD-L1 inhibition, and thus these findings have been translated into the development of immune checkpoint combinations with DDR inhibition [29,30]. Lamberti et al. [31] review the biological rational and current evidence supporting the multiple combinations that are and have been tested including anti PD-1/PD-L1 antibodies with PARP inhibitors, ATR, WEE-1 and CHK1 inhibitors aiming to improve ICI efficacy. Currently, there are no clinically available standard treatment regimens with these combinations; however, if the immunogenic effect of DDR modulation observed in preclinical models is validated in the clinical setting, this combination strategy may provide new options for patients with cancer for which single-agent immune checkpoint blockade is ineffective, such as ovarian and prostate cancers.

Combining radiation therapy with immunotherapy in solid tumors

Radiation therapy is a potent stimulant of immune responses by several mechanisms, including tumor infiltrations and priming of T cells, upregulation of MHC-1 presentation of tumor antigens, and rarely inducing immune responses in distant metastasis, a phenomenon coined "abscopal effect”. Exploratory analysis of clinical trials using ICIs suggest that patients previously treated with radiation therapy experienced prolonged survival rates with anti-PD-1 antibodies [32]. In addition, consolidation therapy with the anti-PD-L1 antibody durvalumab following definitive chemoradiation therapy resulted in improved overall survival in patients with unresectable stage III non-small-cell lung cancer [33]. Several clinical trials are studying the effect of combining stereotactic body radiotherapy with immune checkpoint blockade in lung cancer and other solid tumors on disease control rate and survival. In their editorial, Botticella et al. [34] review the current evidence on the synergistic potential of radiation therapy with immunotherapy in the clinical setting.

B-cell epitope peptide cancer vaccines

The development of anticancer vaccines has been challenging, as most cancer vaccines did not result in clinical benefit for patients in the past [35]. Active immunotherapy approaches like B-cell epitope peptide cancer vaccines aim to induce active immune responses by generating autologous antibodies and limit the need to infuse commercial monoclonal antibodies. Prediction of B-cell epitopes using computational methods can identify potential tumor neoantigens that can elicit a natural humoral immune response [36]. Several reviews [37–40] discuss the principles of B-cell epitope peptide cancer vaccines and the development of these vaccines against HER2, HER3, VEGFR, EGFR, IGFR-1 and immune checkpoints like PD-1. If effective, this strategy could be combined with other targeted agents or ICIs to enhance immune responses.

Novel biomarkers to predict immunotherapy outcomes for patients with cancer

Discovering biomarkers to determine optimal combinations with immunotherapy

Currently approved predictive biomarkers for ICI combinations include the expression of PD-L1 by immunohistochemistry and the diagnosis of mismatch repair deficiency. The tumor mutational burden is the amount of somatic mutations per megabase of DNA in coding areas of the cancer genome, and although it has been explored mainly in the setting of immunotherapy combinations in non-small-cell lung cancer, the evidence to support this biomarker is still not robust. Emerging biomarkers that can predict activity or resistance to immunotherapy combinations are currently being explored, including interferon gamma expression signatures, immune cell infiltration and composition of the tumor microenvironment. In addition, different co-mutation patterns have been identified as resistance mechanisms to immunotherapy in non-small-cell lung cancer, such as KRAS–STK11 or KRAS–KEAP1 mutations. In a brief commentary, Teixido and Reguart [41] review the development of predictive biomarkers of efficacy with immunotherapy. In the era of immunotherapy combination strategies, more robust and integrative biomarkers are needed to properly identify patients in a personalized approach to tailor treatments according to the cancer and host individual characteristics.

The emerging role of radiomics as a predictor of immune checkpoint blockade efficacy

The routine implementation of CT scans, MRI and PET-CT in the clinical practice has allowed the monitoring of responses to cancer therapeutics in past decades, mainly by visualizing the extension and involvement of organs and tissues and monitoring the size of tumor lesions [42]. Radiomics is a quantitative imaging analysis that aims to interrogate tumor characteristics (histologic, immunologic and genomic per example) by applying statistical learning to imaging properties of tumors [43]. Radiomic studies have estimated CD8 T-cell infiltration in tumors, response and primary progression prediction risks to immunotherapy [44]. In an editorial, Limkin and Sun [45] comment on the current applications and limitations of radiomics for immunotherapy treatments of patients with cancer. Implementing radiomics in daily clinical practice requires further validation, standardization and reproducibility; however, this useful tool integrated with genomic, immunologic and clinical variables will most likely become a new biomarker of immunotherapy efficacy in the near future.

Patient-specific multiomic models in personalized combination therapy

Diagnostic technologies have evolved immensely to interrogate tumor biology through genomics, epigenomics, transcriptomics, proteomics, metabolomics and microbiomics to provide a comprehensive view of different components of tumors or single-cancer cells and host biology and immunology. All of this data needs to be integrated in a multiomics approach developing workflows and analytical pipelines. This information can be later implemented to predict sensitivity or resistance of cancer cells to different drugs or combinations, toxicity or side-effect profiles and evolutionary patterns of cancers [46]. In their review, John et al. [47] provide a comprehensive overview of multiomic platforms and application in personalized combination therapies. Although still experimental, multiomic approaches may optimize personalized medicine approaches in the future and become accessible to patients in the daily care setting.

Host circulating biomarkers for ICIs

In addition to tumor genomic and immunologic biomarkers for immunotherapy efficacy, several factors are dependent on the host immunity and inflammatory status. Several scores have been developed to assess the impact of inflammation and composition of circulating immune cell populations in the outcomes of patients with cancer [48]. Most scores are prognostic across different therapeutic regimens including immunotherapy, chemotherapy and targeted agents and the predictive role of these circulating host biomarkers is a matter of study. In their editorial, Riudavets et al. [49] discuss the role of circulating immune cells and inflammatory biomarkers in the selection of patients with immunotherapy combinations.

The actual relevance and future potential of immunotherapy combinations for the treatment of patients with cancer relies in achieving improved cure rates when possible and survival lengths preserving the quality of life. To do so, the development of these combinations needs to be integrated with innovative predictive biomarkers to select patients for the best treatment combinations according to unique features of the patients’ cancer and immune system.