Manufacturing Chemist, April 2017

It is not a stretch to say immunotherapy is the future of cancer treatment.

Some estimates put the sale of immunotherapy drugs at $50 billion by the middle of the next decade (up from $6 billion in 2016). The proven success of combining immune system checkpoint inhibitors (ICIs) with oncolytic vaccines and SMAC mimetics is leading to strategic partnerships between pharmaceutical companies large and small. New payload delivery systems that use microbiota may shake up the sector in the coming years. “I cannot imagine that, during the next 10 years, we won’t start to see a dramatic change in the long-term survival of many of the patients with many of the cancers,” says Jeff Bluestone, Director of the UCSF Hormone Research Institute. “We’ve already seen it in melanoma, wherein we’ve gone from 5% 5-year survival to 40% 5-year survival.”1 For many patients that suffer from deadly late-stage cancers, some of whom have spent years on chemotherapy and radiation treatments, immunotherapy is no less than a godsend. Compared with the toxicity of those treatments, immunotherapy has few sideeffects and is a more effective treatment for a growing list of cancers.

Immunotherapy is such a successful cancer treatment that companies slow to adopt immunotherapeutics into their oncology pipelines have seen investments dip — such as the case with Novartis.2 The global cancer immunotherapy market, already substantial in 2016 at $61.97 billion, is expected to rise to $119.39 billion in 2021 at a CAGR of 14%.3 Immunotherapy drug sales that were $6 billion in 2016 are predicted to skyrocket to $50 billion by the middle of the next decade.4 At this point, immunotherapy is the future of cancer treatment — so how does it all work?

Activate, Identify, Train, Engineer, Target and Destroy

Immune checkpoint inhibitors (ICIs): Immunotherapy relies on the modulation and/or the modification of the immune system responses to treat disease. One of the first treatments used to treat cancer, Ipilimumab (also known as Yervoy), is an excellent example of an immune system checkpoint modulator. Ipilimumab blocks the “brake pedal” — the CTLA-4 ligand receptors on T-cells — that function as a checkpoint against an overactive immune response. When something (a ligand on a dendritic cell, for example) binds to the CTLA-4 receptor, CTLA-4 transmits an inhibitory signal to the T-cell. Ipilimumab is an ICI because it binds to CTLA-4 on the T-cell and prevents it from binding to ligands that would halt an immune response. Therefore, when CTLA-4 is blocked, the T-cells remain activated and go off to find foreign objects to attack, such as cancer cells. But, once the T-cells are activated, they must identify the foreign intruder. And for cancer, a disease that proliferates because of its ability to evade the immune system, the interaction between the T-cells and cancer cells is essential. T-cells identify innate bodies with another receptor: PD-1. Cancer cells evade the immune system with PD-L1 surface proteins that lock into the PD-1 receptor, thereby tricking the T-cell into believing that the cancer cell is not a threat.

Two-year survival of deadly late-stage metastasised melanoma after Ipilimumab treatment was at 26%. The most remarkable aspect of many of these therapies is that the survival curve at 3 years flatlines (known as the “tail” of the curve) — 22% of patients get well and stay well. Nivolumab (marketed as Opdivo) entered the market in 2015, an ICI like Ipilimumab that halts and disrupts PD-1 immune system checkpoint by binding to the PD-1 ligand receptor on the T-cell. Because these two immune checkpoint inhibitors (ICIs) work at different immune system checkpoints — Ipilimumab works upstream at T-cell activation, whereas Nivolumab works downstream after T-cell activation — they can be combined for more robust results. In fact, combined treatment of Ipilimumab and Nivolumab, treating deadly late-stage metastasised melanoma, has a 2-year survival rate of 88% — again, another “tail” of the curve.

Cell therapy: Provenge is an FDA-approved cellular therapy treatment that trains a patient's T-cells to recognise cancer cells. Provenge is an autologous cell therapy treatment (autologous cell therapy uses a patient’s own cells whereas allogeneic uses donor cells) that extracts antigenpresenting cells (APCs), incubates and proliferates them with a recombinant protein that resembles an antigen found on the surface of prostate cancer cells. The trained APCs are then reinjected into the patient’s body where they express these antigens to T-cells, which mature to detect and kill cancer cells that would otherwise go undetected.

Another cell-therapy based immunotherapy that has not yet reached FDA approval is genetically engineered T-cells. CAR T-cells are autologous cells that are genetically modified to express specialised chimeric antigen receptors (CAR) that can identify and kill cancer cells (specifically leukaemia, but research will likely move this technology into other cancers). Allogeneic (from a donor) immunotherapy treatment is a milestone that many researchers believe will make it to the clinical stage in the next decade. In February, FDA approved Cellectis’s IND for a Phase I study of UCART123 in acute myeloid leukaemia and blastic plasmacytoid dendritic cell neoplasm. Off-the-shelf allogeneic immunotherapy, because of its scalability, would cause a pivot in the pharmaceutical paradigm that recently transitioned to a more personalised approach to treatment.

Vaccines: Another promising area in cancer immunotherapies is oncolytic viruses. These viruses have a high specificity for cancer cells. The name “oncolytic” breaks down to “onco” referring to cancer, and “lytic,” which means lyse. These viruses work like any other virus in that they take over the cell’s own machinery to reproduce, and then lyse the cell after it reaches critical mass. Lysing the cancer cell, besides being good in the fight against cancer itself, has an added benefit of releasing antigens into the body. These antigens are detected by APCs that direct T-cells to the location of tumours. This ability to target and destroy cancer cells could be a naturally occurring characteristic of certain viruses, or it could be genetically engineered into a virus to target specific cancer cells.5

SMAC mimetic: A cancer cell’s ability to avoid apoptosis (cell death) is controlled by a set of proteins called inhibitors of apoptosis. Smallmolecule inhibitors of apoptosis antagonists, called SMAC mimetic compounds target this particular pathway and sensitise cancer cells to undergo cell death.6

Exciting Prospects in Combinational Therapies

According to Jill O'Donnell-Tormey, CEO of the Cancer Research Institute: “The field is moving toward personalised, combinational immunotherapy.”7 Seeing the success of combinational immunotherapies, as previously mentioned in the Nivolumab/Ipilimumab example above, many larger firms that cashed in on PD-1 and PD-L1 checkpoint inhibitors — such as Roche, Bristol Myers-Squibb, Pfizer and Merck and Co. — are now trying to make their own combinational, all-in-one immunotherapies that use two or more of the above immunotherapies in concert. As all of the above therapies work on different mechanisms of the immune system, they could logically be used in tandem to create a multifaceted and enhanced immune response to fight cancer.

For example, Pfizer recently partnered with Ignite Immunotherapy, a company that has developed “proprietary oncolytic vaccine products for IV administration that efficiently lyse cancer cells directly and induce systemic anticancer immunity in combination with immune checkpoint inhibitors.”8 In this treatment, T-cells can recognise cancer cells because of the PD-1 ICI, and because the oncolytic virus lyses the cancer cells, more antigen is present for APCs, which activates more specialised T-cells. Often, these combinational therapies are more than the sum of their parts. Last month, researchers at the Children's Hospital of Eastern Ontario in Ottawa found that combining SMAC mimetics and ICIs amplified the kill rate of glioblastoma tumours — the most common form of brain cancer. The treatment in animal models, which are not always translatable to humans, was also highly effective against breast cancer and multiple myeloma. In 2014, the same team published results on the synergistic effects of combining oncolytic vaccines with SMAC mimetics — the latest study shows the same synergistic effects with ICIs.9

Future Directions and Limitations

The latest developments in cancer immunotherapy are the genetically engineered bacteria that, like oncolytic viruses, are tumour killers that direct the immune system response to the site of a tumour. These bacteria can also be modified to deliver therapeutic payloads.10 However, these methods are still in early stages of development. Although the buzz around cancer immunotherapies is certainly warranted, survival rates are still far from 100%, and many of the available treatments only work for a particular type of cancer. In the next several years, pharmaceutical firms will hone in on a combinational therapy that either works for the majority or is a personalised approach to immune profiles based on a patient’s genotype, or on the make-up of a patient's microbiome, which has recently been implicated in the varied efficacy of immunotherapies.11

Either way, the future of cancer treatment in the era of advanced immunotherapy is much brighter than even a decade ago.

References

  1. www.pbs.org/newshour/bb/cancer-immunotherapy-lifesaving-powers-limits/ (8 February 2017)
  2. www.reuters.com/article/us-novartis-harvardidUSKBN1683Q1 (1 March 2017).
  3. www.marketsandmarkets.com/PressReleases/cancerimmunotherapy.asp (September 2016).
  4. www.marketsandmarkets.com/PressReleases/ immunotherapy-drug.asp (January 2017).
  5. N. Woller, et al., "Oncolytic Viruses as Anticancer Vaccines," Frontiers in Oncology 4 (2014): doi: 10.3389/fonc.2014.00188.
  6. S.T. Beug, et al., "Smac Mimetics Synergize with Immune Checkpoint Inhibitors to Promote Tumour Immunity Against Glioblastoma," Nature Communications 8 (2017): doi: 10.1038/ncomms14278.
  7. J. O'Donnell-Tormey, “Immunotherapy: Revolutionizing Cancer Treatment,” Focused Ultrasound Foundation: www.youtube.com/watch?v=VHUnlzpYi1g (18 January 2017).
  8. www.igniteimmunotherapy.com (1 March 2017).
  9. www.sciencedaily.com/releases/2017/02/ 170215101427.htm (15 February 2017). 10. J.H. Zheng, et al., “Two-Step Enhanced Cancer Immunotherapy with Engineered Salmonella typhimurium Secreting Heterologous Flagellin," Science Translational Medicine 9(376): doi:
  10. 1126/scitranslmed.aak9537 (2017).
  11. www.sciencedaily.com/releases/2017/02/ 170221222752.htm (15 February 2017)