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European Biopharmaceutical Review

Therapy for the Soul

Developments in biologic cancer therapies have recently shown promising progress, however the design of these clinical trials may be hindering crucial advancements

Biological therapies encompass a range of agents including antibodies, antibody derivatives (Bi-specifi c T cell engagers, scFv), vaccines (DNA, peptides, cell), oncolytic viral therapy and cell therapies (adoptive T cell therapies and chimeric antigen receptor transuded T cells) (1). The hope is that these agents will yield the sustained disease response which, so far, has eluded traditional cytotoxic cancer therapy.

Recent experience with biological therapies is encouraging. Antibodies that modulate the immune system (for example, anti-PD1 and anti-CTLA4) have given rise to durable long-term responses of more than a year in some patients (2). Furthermore, adoptive T cell and chimeric antigen receptor transduced T cell therapies appear able, under some circumstances, to bring about long-term remission (3, 4). Despite these recent encouraging results, the history of biological therapy has been littered with failure (5, 6).

There are numerous reasons why success in the laboratory does not always translate to the clinic. Broadly speaking, these fall into one of two groups: a) failure to correctly translate the preclinical data to the clinic; or b) failure to adopt an appropriate clinical design.

Failure to Translate Data

The chaotic vasculature makes drug delivery inefficient, and the absence of a lymphatic system in the tumour results in elevated interstitial pressure. These factors limit the ingress of biological therapy into the tumour. Tumour is a hypoxic environment and oxidative stress can result in a reduction of key proteins such as chemokines, T cell receptors and major histocompatibility complex (MHC) molecules, which in turn ablates their anti-tumour activity (7). Additionally, hypoxia skews the immunological profile of the tumour to give rise to an immunosuppressive environment (8).

Failure to understand these aspects of tumour biology may explain some clinical failures. For example, chemokine gradients may be abolished by chemical reduction impeding the influx of cytotoxic T cells following adoptive immunotherapy or cancer vaccination. Antibody therapy dependent upon antibody dependent cell mediated cytotoxicity can also be sensitive to this phenomenon, as the mechanism of action is reliant on the presence of an adequate number of host natural killer (NK) cells in the tumour.

Biological therapies are often species-specifi c; an antibody might not be effective in an animal model if the model lacks a crossreacting
antigen. For example, the human cancer antigen CEA has no homologue in either rats or mice (9). The International Conference on Harmonisation (ICH) guidelines for developing cancer drugs and biological therapies suggest that a therapy should be evaluated in two relevant animal species (10, 11). In the absence of CEA expression, any safety data gained from a rodent animal species with a CEA-directed therapy would be misleading. If the target is expressed in the test species, what is the overall tissue cross-reactivity and how does it compare with human tissue cross-reactivity? Failure to appreciate tissue distribution and cross-reactivity with proteins closely related to the target could lead to misleading assumptions on safety and efficacy that are erroneously applied to the design or interpretation of data arising from the clinical trial.

The value of rodent models of effi cacy (for example, athymic mice carrying a CEA expressing cancer cell line) which are most commonly used in cancer research will be dependent on the putative mechanism of action. We must ask ourselves questions such as: Would a humanised antibody necessarily activate mouse NK cells? Would a human vaccine be processed in mouse and human dendritic cells in the same way? Are the consequences of modulation of the target in the animal model and human identical?

The selection of appropriate animal models is essential for subsequent success in the clinic. Surrogate therapies or transgenic animal models are useful. However, these models cannot always recapitulate every relevant aspect of the clinical situation. As a result, they are more often, although not exclusively, used in a supportive rather than a pivotal role in any clinical trial application. Therefore, a holistic approach to the translation of the therapy from the laboratory to the clinic is required.Investigators should understand the overlaps that exist between test species and patients and, more importantly, where the discrepancies are. This will ensure that the clinical trial protocol is appropriately designed, with the relevant risk management plans in place. Regulatory toxicology and safety pharmacology studies should be used alongside efficacy studies to help formulate a starting dose and dosing schedule. Often, the preclinical package will not resolve all the safety issues. This is not necessarily an issue in Phase 1 clinical trials in late stage cancer patients, where there is a favourable risk benefit profile in allowing patients access to novel therapies. Indeed, the regulatory opinion in the EU acknowledges this,and guidance is available to support the clinical development of such therapies (12).

Failure to Adopt an Appropiate Clinical Design

Cancer Research UK is the largest non-government-funded cancer research charity in the world, supporting over 500 academic research groups active in basic, translational and clinical research. The Drug Development Office (DDO) sponsors the charity’s Phases 1-2a clinical trials, and their projects come from academia and industry through the Clinical Development Partnership scheme (13, 14). Of the 100 or more projects that the DDO has managed, six – including Temozolamide and Abiraterone – went on to gain Marketing Authorisations. In addition to small molecules, the DDO is involved in the development of biological therapies including peptide and DNA vaccines, cellular therapy and oncolytic viruses, as well as antibody and protein-based therapeutics.

The following discussion summarises those issues that, based on previous experience, the DDO feels require special attention when designing clinical trials for biological therapies in cancer patients.

Patient Population
When designing biological cancer therapy clinical trials, we must consider whether patients can be stratifi ed to enrich the trial using only individuals whose tumour expresses the target. It is also important to decide the point in the patient’s journey in which the intervention would work best. For example, cancer vaccination is most effective with residual/indolent disease. Therefore, would a clinical trial in late stage cancer patients with a significant disease burden give rise to a clinical response of sufficient magnitude to persuade a sponsor to continue with its development (15)?

Concomitant Therapies
In an ideal world, an experimental therapy would be given in isolation. This may not be practical with very aggressive cancers such as glioblastoma. In which case, the experimental therapy may be given alongside the standard of care (SoC). What is the impact of this on both the experimental agent and the prescribed medication? Cancer vaccines are a good example of this conundrum. If delivered alongside a cytotoxic drug, will the resultant myleosuppression blunt the immune response, or could the cytotoxic drug actually increase the immune response, for example, by selectively inhibiting regulatory T cells (16)?

Dose Schedule
How frequently does the experimental therapy need to be administered? This might be quite simple in the case of an antibody and dictated on a pharmacokinetic assessment. What about cancer vaccines? What is the optimum frequency which would give a protective immune response to a weak tumour associated antigen?

Measurement of Response
Due to the low statistical power of Phase 1-2 trials, neither Overall Survival (OS) or its surrogate Progression-Free Survival (PFS) are valid markers of response (17). Even in those trials that have adequate statistical power, many biological therapies, particularly immunotherapy, show no change in PFS, despite an improved OS compared with SoC (18).

Response Evaluation Criteria in Solid Tumours (RECIST) are used to measure the response of a solid tumour to experimental therapy. The criteria remove patients from trial when disease progression is confirmed. Biological therapies, particularly those that target or make use of the body’s immune system, often show a delayed response to an intervention. Indeed, pseudoprogression is a common phenomenon with these types of therapy. It is conceivable that a patient may be withdrawn from a trial with a biological therapy when in fact they are
benefiting from treatment. In answer to this conundrum, the use of immune RECIST criteria should be considered wherever a therapeutics mechanism of action significantly exploits the body’s immune system (19).

More frequently, biomarkers of response are selected to demonstrate proof of mechanism in Phase 1-2 trials. These can be markers of tumour burden such as Ki67, PCNA, CA-125 and so forth, or mechanistic markers to demonstrate that the particular intervention is modulating the appropriate host pathways – for example, tetramer or ELIspot assay in the case of cancer vaccines (20). However, the validation status of any biomarkers needs to be carefully and prospectively assessed to ensure that there is adequate justification for the claim that it is being used to support.


In summary, recent developments in biological therapies hold promise that they might bring about significant improvements to patient care. However, the complexity of this therapeutic class means that pre-clinical and clinical scientists must work closely together to successfully translate these drug entities into clinical development. Failure to do so will inevitably lead to the premature termination from development of many promising new therapies.


1. Franks HA, Wang Q and Patel PM, New anticancer immunotherapies, Anticancer Res 32(7): pp2,439-2,453, 2012

2. Lipson EJ et al, Durable cancer regression off-treatment and effective reinduction therapy with an anti-PD-1 antibody, Clin Cancer Res 19(2): pp462-468, 2013

3. Louis CU et al, Antitumor activity and long-term fate of chimeric antigen receptor-positive T cells in patients with neuroblastoma, Blood 118(23): pp6,050-6,056, 2011

4. Kalos M et al, T cells with chimeric antigen receptors have potent antitumor effects and can establish memory in patients with advanced leukemia, Sci Transl Med 3(95): p95ra73, 2011

5. Rao B et al, Clinical outcomes of active specific immunotherapy in advanced colorectal cancer and suspected minimal residual colorectal cancer: a meta-analysis and system review, J Transl Med 9: p17, 2011

6. Wang J et al, Strengths and weaknesses of immunotherapy for advanced non-small-cell lung cancer: a meta-analysis of 12 randomized controlled trials, PLoS One 7(3): pe32695, 2012

7. Lu T and DI Gabrilovich, Molecular pathways: tumor-infiltrating myeloid cells and reactive oxygen species in regulation of tumor microenvironment, Clin Cancer Res 18(18): pp4,877-4,882, 2012

8. Palazon A et al, Molecular pathways: hypoxia response in immune cells fighting or promoting cancer, Clin Cancer Res 18(5): pp1,207-1,213, 2012

9. McCuaig K et al, Expression of the Bgp gene and characterization of mouse colon biliary glycoprotein isoforms, Gene 127(2): pp173-183, 1993

10. Preclinical safety evaluation of biotechology-derived pharmaceuticals, Addendum to ICH: S6(R1), 2009

11. Jones PS and Jones D, New regulatory framework for cancer drug development, Drug Discov Today 17(5-6): pp227-231, 2012

12. Guideline on strategies to identify and mitigate risks for first-in-human clinical trials with investigational medicinal products, EMA, 2007. Visit: swp/2836707enfin.pdf

13. Williams RJ, Walker I and Takle AK, Collaborative approaches to anticancer drug discovery and development: a Cancer Research UK perspective, Drug Discov Today 17(5-6): pp185-187, 2012

14. CRT, Clinical Development Partnership, 2013. Visit:

15. Gulley JL, Madan RA and Schlom J, Impact of tumour volume on the potential efficacy of therapeutic vaccines, Curr Oncol 18(3): ppe150-157, 2011

16. Emens LA, Chemoimmunotherapy, Cancer J 16(4): pp295-303, 2010

17. Di Leo A, Bleiberg H and Buyse M, Overall survival is not a realistic end point for clinical trials of new drugs in advanced solid tumors: a critical assessment based on recently reported phase III trials in colorectal and breast cancer, J Clin Oncol 21(10): pp2,045-2,047, 2003

18. Cheever MA and Higano CS, PROVENGE (Sipuleucel-T) in prostate cancer: the first FDA-approved therapeutic cancer vaccine, Clin Cancer Res 17(11): pp3,520-3,526, 2011

19. Wolchok JD et al, Guidelines for the evaluation of immune therapy activity in solid tumors: immune-related response criteria, Clin Cancer Res 15(23): pp7,412-7,420, 2009

20. Hoos A et al, Improved endpoints for cancer immunotherapy trials, J Natl Cancer Inst 102(18): pp1,388-1,397, 2010


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David Edwards is a Non-Clinical Safety Manager and Clinical Project Manager in the Drug Development Office at Cancer Research UK. He is a member of the small team of translational scientists responsible for the non-clinical safety and efficacy aspects of each clinical trial application, as well as providing input into clinical trial design and authorship of regulatory documentation. David holds a BSc in Biological
Chemistry from the University of Leicester, an MSc in Radiation Biology from the University of London and a PhD from the Faculty of Medicine at the University of Uppsala, Sweden.
David Edwards
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