Combination Immunotherapy: An Emerging Paradigm in Cancer Therapeutics

December 15, 2015

In view of the potential for durable responses with immunotherapy, it will be important to identify the most effective and least toxic regimens for individual patients.

In this issue of ONCOLOGY, Dr. Tchekmedyian and colleagues provide a comprehensive overview of many of the novel combinations of immunotherapeutic agents under development for the treatment of various tumor types.[1] They present a clear conceptual framework for understanding different immunotherapy strategies, and highlight the complexity of immunotherapy by illustrating the vast array of immune-based and non–immune-based approaches that can enhance the antitumor immune response-including checkpoint inhibitors, vaccines, chemotherapy, small molecules, T-cell engineering, and radiotherapy. With a staggering number of agents and combinations under investigation, a rational approach is essential to prioritize the best treatments for individual patients and specific tumor types.

The impetus for these new strategies stems largely from clinical studies that have shown the early but compelling activity of dual blockade of cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4) and programmed death 1 (PD-1) (through combination therapy with ipilimumab and nivolumab) in several tumor types. In CheckMate 067, a phase III, 945-patient clinical trial in advanced melanoma, an objective response rate (ORR) of nearly 60% and a median progression-free survival time of 11.5 months were reported for patients treated with nivolumab plus ipilimumab, compared with 6.9 months and 2.9 months, respectively, for patients treated with nivolumab or ipilimumab alone.[2] These and other results have led to the recent accelerated US Food and Drug Administration (FDA) approval of combination therapy with nivolumab and ipilimumab in advanced melanoma. Similarly compelling results were presented in September at the 16th World Conference on Lung Cancer, where preliminary phase I study data from the nivolumab-plus-ipilimumab arm of CheckMate 012 ( identifier: NCT01454102) revealed ORRs ranging from 13% to 39% in patients with chemotherapy-naive advanced non–small-cell lung cancer (NSCLC). Finally, early study results in patients with advanced renal cell carcinoma demonstrated response rates ranging from 29% to 39% for treatment with the combination.[3] These results with dual checkpoint blockade of CTLA-4 and PD-1 will serve as a standard for rational trial design in future investigations of immune combination therapy.

As we move forward into this exciting era of cancer immunotherapy, the answers to several major questions will facilitate successful translation of these combination therapies into the clinical setting. One particular gap in our knowledge is the lack of accurate biomarkers to predict which patients will likely respond to various single agents or combination therapies. This will become paramount as additional effective combinations and sequences undergo clinical development. It remains unclear what separates subsets of patients with exceptional responses from those who fail to respond.

Currently available biomarkers have suboptimal predictive capacity. The most studied marker, expression of programmed death ligand 1 (PD-L1) on tumor or infiltrating immune cells, is associated with higher response rates in most clinical trials across many tumor types. However, the lack of a standardized definition of positivity and technical aspects of multiple available assays are barriers to clinical implementation. Furthermore, despite the modest correlation of PD-L1 expression with response, ORRs of 5% to 20% still occur in PD-L1–negative patients. In our opinion, negative PD-L1 expression should not be used to exclude patients from anti–PD-1 therapy in most cases. However, lack of expression could guide clinicians toward combination therapy (eg, with nivolumab plus ipilimumab), which appears to be more effective in PD-L1–nonexpressing melanoma patients. In the future, this marker could also be considered as a means of stratifying patients into subgroups who would benefit more from alternative combinations.

Numerous translational studies have also identified other promising biomarkers. One approach includes whole-exome sequencing to quantify mutational load in patients treated with CTLA-4 or PD-1 blockade. In these studies, higher mutational load and higher numbers of neoantigens have been associated with improvements in response rates and overall survival in patients with melanoma.[4] This association with mutational load has been seen across tumor types in mismatch-repair–deficient tumors and NSCLC.[5,6] Additionally, there is evidence that higher density of preexisting T-cell clonal expansion and PD-1–positive, CD8+ T cells located at the invasive tumor margin are associated with tumor regression and response after PD-1 blockade.[6] This suggests that PD-1/PD-L1 blockade may be more beneficial in tumors where there is histologic evidence of preexisting adaptive immune resistance. Ultimately, these or other markers may be used clinically to guide selection of various immune therapy regimens.

Another important consideration will be the unique toxicity profiles that these combinations may present. Clearly, combination of the checkpoint inhibitors nivolumab and ipilimumab can increase the risk and severity of immune-related adverse events, such as pneumonitis, hypophysitis, hepatitis, and colitis. In the CheckMate 067 trial, 55% of patients receiving the combination therapy experienced grade 3/4 treatment-related adverse events.[2] Although most of these toxicities are self-limited and resolved with immune-modulating medications, we must be mindful of the potentially lethal consequences of immune overstimulation, as demonstrated by CD28 stimulation[7] (and as noted by Dr. Tchekmedyian and colleagues). The need to find an optimal safety and efficacy profile for combination immunotherapy strategies is being addressed in recent phase I trials, including CheckMate 012 and CheckMate 032 ( identifier: NCT01928394), which used varying doses and schedules of ipilimumab and nivolumab.

While Dr. Tchekmedyian and coauthors do a commendable job of reviewing immune therapy combinations, one important approach was omitted: the combination of immune checkpoint inhibitors with oncolytic viruses. Talimogene laherparepvec (T-VEC) is a modified, injectable herpes simplex virus that produces an immune response against both directly injected melanoma tumors and distant metastases. This agent recently received single-agent FDA approval as a treatment for advanced melanoma. In a study in which T-VEC was administered in combination with ipilimumab, 41% of patients (7 of 17) experienced an objective response ( identifier: NCT01740297). A study combining T-VEC with pembrolizumab is also ongoing ( identifier: NCT02263508).

In view of the potential for durable responses with immunotherapy, it will be important to identify the most effective and least toxic regimens for individual patients. The numerous combination trials and translational research developments highlighted by Dr. Tchekmedyian and colleagues provide an important opportunity to answer many critical questions that we hope will bring our patients closer to the elusive goal of cure.

Financial Disclosure: Dr. Johnson serves on advisory boards for Bristol-Myers Squibb and Genoptix. Drs. Wang and Sosman have no significant financial relationship with the manufacturer of any product or provider of any service mentioned in this article.


1. Tchekmedyian N, Gray JE, Creelan BC, et al. Propelling immunotherapy combinations into the clinic. Oncology (Williston Park). 2015;29:990-1002.

2. Larkin J, Chiarion-Sileni V, Gonzalez R, et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med. 2015;373:23-34.

3. Hammers HJ, Plimack ER, Infante JR, et al. Phase I study of nivolumab in combination with ipilimumab in metastatic renal cell carcinoma (mRCC). J Clin Oncol. 2014;32(suppl 5s):abstr 4504.

4. Snyder A, Makarov V, Merghoub T, et al. Genetic basis for clinical response to CTLA-4 blockade in melanoma. N Engl J Med. 2014;371:2189-99.

5. Le DT, Uram JN, Wang H, et al. PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med. 2015;372:2509-20.

6. Tumeh PC, Harview CL, Yearley JH, et al. PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature. 2014;515:568-71.

7. Suntharalingam G, Perry MR, Ward S, et al. Cytokine storm in a phase 1 trial of the anti-CD28 monoclonal antibody TGN1412. N Engl J Med. 2006;355:1018-28.