Three Generations of Cancer Immunotherapies

From CTLA4 to PD1 to the next generation

Since the regulatory approval of ipilimumab in 2011, the field of cancer immunotherapy has been experiencing a renaissance. An article published in the Nature Reviews Drug Discovery explores the changing drug-development paradigm, clinical practice altering data, the broad range of immunotherapy agents and key emerging trends: changes in standard of care, improvement of endpoints and research methods, immune biomarker development, rational combination strategies and expansion of the toolbox of novel immune therapies.

Owing to its potential for a large and sustained clinical benefit, this area became the fastest-growing area not only in oncology but in the entire pharmaceutical industry. Despite this success, the field of onco-immunology is still young and much potential for growth and substantive translational and clinical improvements exist. The emerging therapies can be categorised into three generations.

Generation 1 encompasses the initiating agents in onco-immunology era, ipilimumab and sipuleucel-T, which were approved based on survival improvements in randomised phase III trials in 2010 (sipuleucel-T) and 2011 (ipilimumab). Sipuleucel-T did not become a commercial success owing to the complexities of scaling production and commercializing this autologous cell therapy; however, it provided important lessons on the regulatory, chemistry, manufacturing and controls and commercial aspects of onco-immunology drug development.

At the centre of generation 2 of onco-immunology agents are PD-1 and PD-L1 blocking antibodies. The first PD1-targeted agents – pembrolizumab and nivolumab – were approved by the US Food and Drug Administration (FDA) and the European Medicines Agency in 2014 (pembrolizumab) and 2015 (nivolumab) and the anti-PD-L1 agents atezolizumab and durvalumab are in pivotal clinical trials (with atezolizumab being just approved by FDA for the treatment of urothelial cancer). Pembrolizumab achieved approval in record time, after only 4 years of clinical development. Blinatumomab, a bi-specific T cell engager targeting CD19-positive B cell malignancies, was approved in 2015. Moreover, autologous cell therapies that target CD19 using chimeric antigen receptor (CAR)-transduced T cells (CAR-Ts) are being developed. CAR-Ts emerged with promising clinical data in CD19-positive malignancies; in some studies durable response rates as high as 90% were reported. Talimogene laherparepvec (T-vec), an oncolytic viral therapy, was approved for local injection in unresetable melanoma, recurrent after initial surgery.

The next wave of therapies can be summarised as third-generation agents that result from the broad expansion of onco-immunology across multiple mechanisms and modalities, and this generation of therapies may be the most competitive yet.

To date, most of the activity, in the field of cancer immunotherapeutic modalities, has concentrated on the T cell area. The second branch of the adaptive immune system, B cell immunity, has not yet received much attention for therapeutic purposes. However, it has certainly proven its utility for prophylactic vaccination against infectious diseases. Innate immunity targets and drugs (for example, natural killer cell targeting therapies) are gaining great interest, and novel approaches are emerging. Overall, the variety of modalities under investigation include cytokines, cell therapies (including genetically engineered cells), checkpoint modulatory antibodies, cancer vaccines, BITEs that direct T cells to cancer cells (connectors), dual-specific antibodies that integrate two targeting moieties into one molecule, small molecules, oncolytic viruses and immune adjuvants (for example, toll-like receptor agonists).

This wide range of modalities can be used in various ways to stimulate anticancer activity across the different branches of the immune system. It is likely that these new immunotherapies will enable further improvements over the already successful generations 1 and 2. The substantial improvements in survival observed with checkpoint-modulating immunotherapies are starting to change standards of care in oncology. This trend was initiated by first and second generation agents and will probably continue with generation 3. New modalities, such as CAR-Ts are already showing attractive clinical results. However, these new modalities may also carry new toxicity risks, such as the potential for induction of a cytokine storm and cross-reactivity with healthy tissue.

Overall, this trend will probably substantially change the oncology treatment landscape. The potential for cure, either on a functional level by turning cancer into a controllable chronic disease (similar to achievements with HIV drugs) or in the true eradication of the disease, may now be a prospect for large number of patients with cancer. Much is needed to achieve this; however, the field of onco-immunology is moving rapidly, the directions are reasonable clear and the outlook for cancer drug development has never been better.


Hoos A. Development of immuno-oncology drugs – from CTLA4 to PD1 to the next generation. Nature Reviews Drug Discovery 2016;15(4):235-247.