New drugs for colorectal cancer - Highlights of 2015 and 8 drugs to watch

Colorectal cancer highlights of 2015

• Tumours laden with more mutations may respond better to immunotherapy. Perhaps one of the more quoted studies of 2015 was the trial of Merck’s drug Keytruda, in colorectal cancer, which demonstrated that colorectal tumours with higher mutational burden responded better to this new immunotherapy drug. High mutation tumours shrank 60% of the time compared to zero shrinkage in tumours with few mutations. The classic kinase inhibitors, might result in better responses for tumours with fewer mutations.

• A different set of toxicities (colitis, pneumonitis, hepatitis etc.) is emerging. This is in contrast to the type of chemotherapy side effects where we were accustomed to dealing with effects such as hair loss since chemotherapy affects all cells that divide quickly.

• There is a tail on the curve with immunotherapy treatments which can show high response rates even when the median response for that type of patient is low. A patient who has only a 10% chance of responding with immunotherapy rather than 60%, may still want to try immunotherapy - since standard chemotherapy might give the patient a chance of survival that is close to zero. Identifying patients whom might benefit from the tail on this curve could be one of the surprises on the immunotherapy horizon, especially as we identify which biomarkers cause high responses with immunotherapy.

• Emergence of patients with certain biomarkers and molecular subtypes who respond better to immunotherapy, vaccines and other treatments like new stem agents. For instance, research in 2015 has shown that patients respond better to immunotherapy depending upon whether they have a certain molecular subtype of lymphoma (a study from the National Cancer Institute in the US), or lower CD68 macrophages in lymphoma (a phase 2 study from the Nordic community). The low CD68+ group in the Nordic study had favourable overall survival rates of 90% when taking chemoimmunotherapy versus only 60% when taking chemotherapy alone. Refer to lymphoma for more. Refer to drugs for high Nanog and MAGE-A biomarkers in colorectal cancer below.

• The categorisation of gastric tumours related to the Epstein-Barr virus from The Cancer Genome Atlas (TCGA) work, which has become an important guideline for developing new therapeutics. Epstein-Barr virus related gastric tumours made up 9% of gastric tumour types in a study (see colorectal cancer). These tumours did not have many mutations, however PDL1 and PDL2 expression was high. This may explain why some cancer patients respond better to some of the anti-PDL1 immunotherapies, despite that the mutational load was low. Recall that patients tend to respond better to immunotherapy when they have the expression of the PDL1 molecule on cancer cells.

• The theory that only cancer stem cells lead to metastasis (spreading of cancer), although the tumour microenvironment is important too. Doctors Wicha and Shah discuss this in ‘Key concepts in targeting cancer stem cells’ [1] - a video review on the Medscape app on 30th October 2015. It is suggested this fraction of cells, are the only ones that can form tumours when you implant them. They suggest that cancer stem cells are responsible for all metastases [2]. In this model cancer stem cells are the seeds of cancer and the tumour microenvironment is the soil, which regulates cancer stem cells and includes distant organs cancer has metastasized to. Refer to stem cells for more.

In colorectal cancer there are a few notable drugs or companies who are developing immunotherapies, including new vaccines in Phase 3 trials that attain better response rates with virtually no toxic side effects, a new stem cell agent which tackles the elusive cancer stem cell; and a preventative program that uses a drug already in use for African sleeping sickness and excessive hair growth. There is also new technology from Adaptive in the T cell receptor space (TCR, see definitions below) that may help us be more precise in using our immune system to target cancer cells. See below.

• Biothera's Imprime PGG in phase 3 trials. In Phase 2 they showed a response rate of 24% vs 11% and progression free survival of 12 weeks versus 6 weeks in 111 patients with colorectal cancer. In an online presentation arranged by Nature magazine on 21 July 2015 Biothera spoke about the importance of cancer cells having PD-L1 expression on their surfaces - programmed death ligand one - and said they are showing in vitro (in the test tube), that their agent can spark the expression of PD-L1 on the surface of cancer cells, including lung, breast and pancreatic cell lines. Refer colorectal cancer for more detail. Biothera also showed results in lung cancer (see lung cancer) and chronic lymphocytic leukemia (see lymphoma). Northwest Biotherapeutics with their vaccine DCVax-direct said they saw an immune response of PD-L1 expression in 64% of 39 evaluable patients with all types of inoperable solid tumours. These trials are however in the very early stages and the share price fell in December 2015 after a "Phase 5 report" said they were shorting the stock and questioned the long standing trials and reliability of the data in the glioblastoma trial; including that the endpoint was changed from overall survival (OS) to progression free survival (PFS).

• Boston Biomedical's BBI608, a cancer stem cell agent in phase 3 trials that blocks cancer stem cell renewal and survival by suppressing stemness pathways. These pathways include STAT3, β-catenhin and immune checkpoint gene expression. A response of 50% in patients who had had one prior therapy was observed in phase 2 gastric and gastroesophageal junction trials of 6 patients. BBI608 also achieved results in various phase 1b/ 2 colorectal trials including one combination trial of 24 patients with BBI608-224 and chemotherapy; where the combination achieved disease control of 53% versus 44% in the control group. The company suggested BBI608 may resensitize patients to repeat anti-EGFR therapy i.e. to chemotherapy. This activity was discussed by Dr's Wicha and Shah (Key concepts in targeting cancer stem cells’ [1]) with reference to epithelial to mesenchyl transition (EMT) where cells go back and forth between the two states.

• Boston Biomedical also have BBI503, currently in Phase 2 trials where disease control rate (DCR), in evaluated patients with high Nanog biomarker-positive status was 55.6%, while DCR in biomarker-negative patients was 12.5%. Median overall survival in biomarker-positive patients was 38 weeks compared to 15.9 weeks in biomarker-negative patients so the agent may show promise if similar results can be achieved in Phase 3 trials. Although we shrink and debulk colon cancer with chemotherapy, we don’t actually cure it with chemotherapy, according to the discussion held with Drs Wicha and Shah [1]. Adding cancer stem cell agents to the cocktail of treatments may deal with fractional cancer stem cells that persist (see stem cells).

• Merck's Keytruda where objective response rates of 60% were observed in phase 2 trials of tumours with many mutations in mismatch repair, compared to a zero response rate when tumours had few mutations in mismatch repair.

• Puma's Neratinib treats lymphocytes (blood cells) with aldesleukin in the lab. Puma, aided by Steve Rosenberg at the National Cancer Institute, hopes this may stimulate the lymphocytes to kill more tumour cells when they are put back in the body after chemotherapy.

• DanDrit Biotec's MelCancerVac (MCV showed 20% (4 out 20 patients) experienced stable disease after taking the vaccine in a trial ending in 2006. A Singapore trial ending in June 2007 of patients with the MAGE-A biomarker showed 40% of patients had stable disease. Progression-free survivals for the patient group were only around 2 months, however 25% of patients (5 patients) had a PFS of more than 6 months and 2 of the patients were still progression free several years later. Moreover no toxicity was observed. In other cancer types lung cancer trials were undertaken and they are in discussions with the NCI to start a combination trials with a PD-1 checkpoint inhibitor in bladder cancer. The lean business model of this Danish-based company with 3 employees with its outsourced manufacturing and trials lends itself to more trials without incurring heavy costs. Dandrit pay royalties for compassionate use programs, which will generate real life data for them. The company has patented a method developed with Bioneer for using microRNAs to characterize dendritic cells and establish a basis for quality control. Also refer to Adaptimmune who have a MAGE target for solid tumours.

• Adaptive Biotechnology sequence T cell receptors. Adaptive can sequence millions of T cell receptors daily in order to predict response to drugs. I find their work on matching antigens (refer definitionsbelow) in cancer cells - to unique and binding T cell receptors - most interesting. The technology is attractive for its ability to develop more specific immunotherapy for cancers.The company takes antigens from tumour cells and then look for a T cell receptor that strongly binds to the antigen. They can sequence millions of T cell receptors and once they find one to target (a clone or a match), they can put that T cell into a viral vector, inject T cells back into patients and let killer T cells kill the molecule they are targeted to kill. This way they find the best T cell receptor to target. We could try and conduct trials for every T cell receptor; or simply ask a computer to try every possible T cell receptor for every possible antigen and it is the latter that offers promise for new therapies. Adaptive technology is in the early stages of development, but if it works it will be a triumph for 'brute force' of machine learning, which Peter Diamandis refers to in his inspiring book 'Bold.'

• Sanofi's Eflornithine and Sulindac by Cancer Prevention Pharma is a combination preventative program in a Phase 3 trial. This drug Eflornithine is already used for African sleeping sickness or trypanosomiasis (a name for several parasitic diseases from tsetse fly bites) and the drug is used to reduce excessive hair growth. It is interesting that a drug that inhibits hair growth - hairs contain fast-dividing cells - might also inhibit cancer cells. The DSMC met in May 2015 and suggested Phase 3 trials continue as planned. In an earlier trial, people who had had adenomas removed from their colon who then took daily Eflornithine and Sulindac for three years lowered their risk of developing another adenoma during the following three years to less than one third of what it was for those who did not take the drugs. And they lowered their chances of developing a high-risk adenoma during that time by 90 percent. Of interest to me is that bacteria such as leishmania can upregulate nicotinamide adenine dinucleotide (NAD), but consume tryptophan. Refer stem cells for an interesting discussion - we need sufficient NAD, but tryptophan can suppress the immune system.

• Xbiotech’s Xilonix On 6th December 2015 announced 33% of the 207 patients randomized to Xilonix treatment met responder criteria, compared to 19% of the 102 placebo patients in its European phase 3 study in advanced colorectal cancer. The stock increased by 50%. Previously they published Phase 2 results in the Lancet on 17th April 2014, showing recovery of lean body mass (muscle mass) in 2/3rd of patients and "dramatic improvements" in overall survival in advanced colorectal patients. Based on these results, XBiotech received Fast Track designation from the FDA in October 2012 to develop Xilonix in the setting of metastatic colorectal cancer (these results I could not find.) The drug neutralises interleukin 1-alpha but without modifications in vitro (in the test tube), which is appealing says the company, given such engineered modifications can cause immunogenicity, infusion reactions, poor performance and other issues. Later the company received criticism for having untraditional endpoints related to cancer symptoms rather than tumour growth.

• Probiotics when AIM2 protein is deficient. New research from the St Jude children’s hospital immunotherapy department indicates a deficiency of the immune protein AIM2, found in colorectal cancer, can also be associated with a deficiency of gut bacteria. Where AIM2 is not deficient, this may ensure sufficient ‘good’ bacteria to protect against colon cancer cells. Notably, a deficiency of AIM2 can also lead to more ‘cancer’ stem cells. This was discussed at the inaugural international immunotherapy conference, September 19th 2015. Refer to the microbiome for more detail on these studies. Man said “We believe that this finding has important clinical relevance because we can potentially prevent or decelerate the progression of colorectal cancer in humans, especially in those who have mutations in the AIM2 gene, by simply giving them ‘good’ microbiota.” (Source: Discovery promises new treatments to thwart colon cancer, Memphis, Tennessee, June 18, 2015.)

• New drugs targeting the Wnt pathway, which is aberrant in around 80% of colorectal cancers and may have a role in establishing and maintaining cancer stem cells within colorectal tumours.

Definitions

*An antigen is a substance that when introduced into the body stimulates the production of an antibody. Antigens can include toxins, bacteria, viruses, foreign blood cells, and cells from transplanted organs.

Antibodies are proteins produced by the body to fight disease and can neutralise antigens by binding to them (source: the free dictionary).

T cells are blood cells, which circulate and fight foreign antigens.

T cell receptors are molecules on the surface of T cells which bind to antigens. Activity of these receptors depend on major histocompatibility complex (MHC) proteins. Turning T cells 'on' to fight cancer is one of the great concerns of immunotherapy today.

NAD is nicotinamide adenine dinucleotide. If the body does not get enough NAD; low tryptophan levels can signal the body to lower the immune system and accept certain bacteria such as Tubercolosis [3].

Questions

In light of the immune link to NAD and the findings that self-renewing cancer stem cells have excess NADH [4], some questions arise:

1) Is it possible that cancer cells lower the immune system in order to store extra NADH? 2) Can we develop drugs that use NADH as a biomarker for cancer stem cells (NADH can be measured by adenine).

3) Can we develop drugs that target faults in the NADH pathway? Moreover to what extent are bacteria or viruses causing 'faults' or conditions in the NADH pathway, for instance lower tryptophan? If we know which viruses or bacteria cause faults we can target faulty pathways more easily. For more on this see our blog on the role of NAD in cancer.

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References

[1] Medscape app ‘Key concepts in targeting cancer stem cells to manage disease’ Max S Wicha, MD and Manish A Shah, MD, CME, Medscape Education oncology, October 30, 2015.

[2] Kaplan RN, Riba RD, Zacharoulis S, et al. VEGFR1-positive haematopoietic bone marrow progenitors initiate the premetastatic niche. Nature. 2005; 438: 820-827. Langley RR, Fidler IJ. The seed and soil hypothesis revisited -- the role of tumor-stroma interactions in metastasis to different organs. Int J Cancer. 2011; 128: 2527-2535. References from Medscape.

[3] 'Big Brains, Meat, Tuberculosis, and the Nicotinamide Switches: Co-Evolutionary Relationships with Modern Repercussions?' Adrian C. Williams and Robin I.M. Dunbar et al. 15 Oct 2013.

[4] 'Exploiting Mitochondrial Dysfunction for Effective Elimination of Imatinib-Resistant Leukemic Cells', Jérome Kluza, Manel Jendoubi et al. July 18 2011.

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