Melanoma immunotherapy: Can vaccines and cell therapies expand on immune checkpoint inhibitor successes?

Mestastatic melanoma cells

Tracking the major cancer meetings has kept me occupied throughout October and into November but left me with plenty of material for this, and future, blog articles. A presentation at the UK’s NCRI conference on the increasing mortality rate from melanoma in men (but not women, where mortality rates are generally declining or stabilising), while alarming, did remind me of just how far melanoma treatment has advanced in a few short years.  

Prior to the availability of anti-CLTA-4 and anti-PD-1 immune checkpoint inhibitors, overall survival from metastatic melanoma in developed countries was around 25% after three years: combination immune checkpoint inhibitor treatment has stretched this to over 60%, and use following surgery (“adjuvant” use) significantly improves recurrence free survival.

Despite these successes, a significant need remains for alternative treatments for those who fail, or are intolerant of, current immune inhibitor checkpoint regimens and a gamut of investigational immunotherapies including “personalized” or “individualised” peptide and mRNA therapeutic vaccines, cell therapies and oncolytic virus therapies are in active clinical development.

That the immune system recognises melanoma as being “not self” has been known for decades and means of usefully exploiting this distinction long precede the discovery of immune checkpoints. Attempts to effectively boost the anti-melanoma immune response through injection of the Bacille Calmette–Guérin (BCG) tuberculosis vaccine were made in the 1970s, with mixed success. The potent immunomodulators, interferon alpha (IFNα) and interleukin 2 (IL-2), were approved for use in melanoma in the 1990s and still have a role in the treatment of metastatic disease and adjuvant therapy.

Melanoma has long been an attractive target for cancer vaccine development. A variety of melanoma antigens common to a majority of tumours - “tumour-associated antigens” (TAAs), including gp100, GM2; tryosinase, MART-1 and MAGE-A3, have been exploited, either alone or in combination, in cell-based and peptide therapeutic vaccines.

Cell-based vaccines (as either intact or processed tumour cells or as cell-free lysates) offer the advantage of presenting a spectrum of TAAs, although neither patient-derived (autologous) nor cultured tumour cell-derived (allogeneic) cell-based melanoma vaccines, such as Melacine® (GSK/Schering) and Canvaxin® (CancerVax/Serono), have made it through pivotal studies. M-VAX (AVAX), a chemically-modified autologous cell vaccine, has been in late-stage development limbo for over a decade.

Historically, peptide vaccines have fared no better, with a pivotal study of Oncophage® (Antigenics), the manufacture of which involved isolation of heat shock protein-peptide complexes from autologous tumour cells, being abandoned, and a Phase III study of a MAGE-A3 peptide vaccine (GSK) being terminated due to lack of obvious efficacy over placebo.

Adoptive cell transfer (ACT) involves the collection, isolation, ex vivo expansion and (re)-infusion of autologous tumour-associated cytotoxic T-cells. ACT using tumour-infiltrating lymphocytes (TIL) has occasionally attained response rates of 40%-50% and complete remission in 10% to 25% of patients with extensive metastatic disease: however, the complexity of ACT has essentially confined it to clinical studies and compassionate use.

As is the case with other cancer indications, decades of disappointment and inconsistency have not curbed the academic and commercial pursuit of effective melanoma immunotherapies. Applying recent advances in technology- next generation sequencing; gene transfer and editing; nucleic acid delivery- to melanoma vaccine and cell therapy development might just make these old dogs capable of new tricks.

Cancer vaccine efficacy is blunted by the immunosuppressive tumour microenvironment: combination with immune checkpoint inhibitors is an obvious means of increasing the odds of success and a number of studies combining therapeutic vaccines with anti-PD-1 or anti-CTLA-4 immune checkpoint inhibitors are underway. These agents may eventually be joined or replaced, by one or more of the “next wave” of immune-oncology drugs directed at LAG3, CSF1-R, GITR or at targets in the innate immune systems which can fire up the immune response.

Imlygic® (T-VEC: Amgen), an oncolytic virus therapy is“vaccine-like” in effect, activating both the innate immune system and revealing hidden tumour antigens (“neoantigens”) to the adaptive immune system through tumour lysis. Combination with ipilimumab has shown improvement in response rates over Imlygic® alone, and a Phase III combination study with pembrolizumab (KEYNOTE-034) is ongoing. Early-stage studies of CAVATAK®, an investigational virotherapy acquired by Merck & Co from Viralytics earlier this year, has shown promise when combined with either pembrolizumab or ipilimumab.

The application of next generation sequencing technology and bioinformatics could offer a practical route to bespoke melanoma vaccines, with antigen selection and vaccine composition being determined by tumour and patient genetic makeup. Neon Therapeutics is currently trialling a synthetic peptide vaccine (NEO-PV-01) using sequencing of tumour biopsy material to formulate a selection of up to 20 peptide-mimicking patient-specific neoantigens. NantBioScience is pursuing a similar personalization strategy, with expression of patient-specific neoantigens in yeast cells (YE-NEO-001).

The in vivo expression of melanoma (and other cancer antigens) through the introduction of the corresponding mRNA sequence is receiving increasing attention. Lipid complex mRNA vaccines, encoding multiple melanoma TAAs or a personalised selection of antigens, are now in early clinical studies (Lipo-MERIT and RO7198457: BioNTech).

mRNA has brought a new twist to dendritic cell (DC) vaccination, where DCs isolated from the patient are loaded with melanoma antigens to optimise their processing and efficiency of presentation to the immune system. eTheRNA’s TriMix technology combines mRNA encoding melanoma antigens with mRNA encoding proteins known to enhance DC activation and maturation and to promote both helper and cytotoxic T cell production. Durable clinical responses have been achieved in melanoma patients who had failed previous treatments when the TriMix-DC-MEL vaccine was administered in combination with ipilimumab.

Gene transfer may open up additional ACT strategies for melanoma. T-cell receptor (TCR) gene transfer allows the generation of antigen-specific lymphocytes from patient T-cells Early studies with melanoma antigen-specific TCRs have shown modest response rates, although several have been marred by severe adverse events due to the “off-target” destruction of normal melanocytes.

The utility of ACT may be significantly improved through chimeric antigen receptor (CAR-T) technology, where T-cell antigen receptors are engineered to combine binding, signalling and co-stimulatory domains. Pilot CAR-T studies are underway. Improvements in TIL ACT may be possible by using CRISPR-CAS9 gene editing to increase the ability of T-cells to home in on tumours.

Next generation cell therapies, including DC vaccination, are likely to benefit from the broader expanding commercial interest in CAR-T and TCR therapies which will likely lead to further improvements in manufacture and assist in establishing the logistics necessary to delivery patient-specific treatments. Growing use of semi- or wholly-automated cell product processing will ultimately reduce costs and make the treatment of larger number of patients viable.

Effective melanoma immunotherapy had been a long time in coming, but as immune checkpoint inhibitor therapy has shown, revolution is possible. Experimental melanoma immunotherapies still have a lot to prove, but with the aid of across the board advances in immuno-oncology and other disciplines, we may finally see vaccine and cell-based approaches becoming practical and valuable treatment options.

Photo credit: Valencia, JC. NCI Center for Cancer Research

Dendritic cell vaccines: back to the future

Dendritic cell (computer generated from
EM scan)

Two news announcements in recent weeks sent me tripping down memory lane and musing on the number of once promising therapeutic concepts that have never lived up to their billing. 

At the turn of the century, dendritic cell vaccination was seen as the great leap forward for cancer immunotherapy. The concept is simple, although execution less so. The body’s recognition of infectious agents or cancer cells as being “foreign” starts with how antigens are presented to the immune system by specialised, wait for it, “antigen presenting cells”, of which dendritic cells (DCs) elicit the most potent T-cell responses. 

DCs can be readily harvested from bone marrow or peripheral blood, primed in the laboratory to recognise tumour antigens, expanded and matured in culture and then infused back into the patient, ready to kick-start a cancer-fighting cellular immune response. The challenge of commercialising DC vaccination proved to be as much logistical as immunological with only one company, Seattle-based Dendreon Corporation, successfully overcoming the hurdles of DC collection, processing and delivering adequate amounts of patient-specific vaccine, all in a manner satisfactory to regulatory agencies.  

Dendreon’s one and only product, Provenge®, received approval as a treatment for hormone-refractory (“castration resistant”) metastatic prostate cancer in 2010. While hailed as a milestone in cancer vaccine development, Provenge® was approved on the basis of a 4 month improvement in median survival over placebo, at a treatment cost of $93,000. Confusion over reimbursement, scepticism over benefit, competition from conventional chemotherapy, low margins and heavy corporate debt resulted in Dendreon filing for bankruptcy at the end of 2014, with Provenge® and the manufacturing assets being first acquired by Valeant in early 2015 and then by Sanpower Group, a Chinese conglomerate, in early 2017. 

Sanpower, while eyeing China and other new markets, is hoping that a new Provenge® study in men with early-stage prostate cancer might lead to an expanded label indication.  Prostate cancer progression is slow is most men, and “watchful waiting” is an option to surgery and/or radiotherapy. Provenge® therapy might usefully slow progression, although proof of this is at least five years away. 

A near-neighbour of Dendreon’s, Northwest Biotherapeutics is another long-standing champion of DC vaccination, its  lead product being DCVax®-L, a personalised vaccine for glioma, an aggressive form of brain cancer. DCs are primed using material from the patient’s own tumour. Northwest has a history that can reasonably be described as “colourful”, involving allegations of related party transactions, mysterious delays in the reporting data from a Phase III study first registered in 2002 (variously attributed to the Christmas holidays and a severe outbreak of flu among senior management), and a subsequent exit from NASDAQ. 

With broad, and misleadingly enthusiastic, coverage in the popular press, Northwest recently provided an update on progress in the Phase III glioma study, now in its 11th year. Well, better late than never, but as others have pointed out, it doesn’t actually say that much, being interim (and blinded) data. The data set stands at 331 subjects (DCVax®-L and placebo-treated) although interpretation is complicated by the cross-over study design, as patients with tumour recurrence (a racing certainty in glioma) were allowed to receive the vaccine. 

A breakdown of survival by factors known to influence outcome (the degree of resection, patient age and the ability to better metabolise chemotherapydrug) hints at an increase in survival , but the conclusion is no stronger than “Collectively, the blinded interim survival data suggest that the patients in this Phase 3 trial are living longer than expected”.  Proof of significant benefit awaits primary outcome data (progression-free survival). 

While a treatment that improves survival in glioma is sorely needed,  and a better-tolerated alternative to chemotherapy might be preferable for some prostate cancer patients, DCVax®-L or Provenge® successes are unlikely to lead to a renaissance in DC vaccine interest, as the spotlight has long since shifted to CAR-T and other cellular immunotherapies, small molecule and biologic immuno-oncology drugs that rekindle anti-tumour immune responses and neoantigen-based cancer vaccine strategies. 

Ironically, without the pioneering work of Dendreon, both in DC vaccine manufacturing logistics and establishing enhanced survival, the industry might never have embraced cancer immunotherapy development with anything like the current degree of enthusiasm. 

Photo credit:  Bliss, D  and Subramaniam, S. National Cancer Institute.

Are IDO inhibitors still the next big thing in immuno-oncology?

Metastatic melanoma cells

It's a safe prediction that immuno-oncology (IO) drug development activity is unlikely to diminish in 2018, with a major objective being the validation and approval of agents that synergise with the established anti-CTLA-4 and anti-PD-1/PD-L1 immune checkpoint inhibitors.

Much has been written on the broad utility of inhibitors of indoleamine-2,3-dioxygenase-1 (IDO), an intracellular enzyme present in both immune cells and cancer cells and  which regulates tryptophan levels in the tumour microenvironment (TME). 

Depletion of tryptophan by upregulated IDO expression starves cancer-antigen specific T cells, while a rise in the concentration of tryptophan metabolites triggers the development of immunosuppressive Treg cells.

This central role in local immunosuppresion and the prospect of synergy with immune checkpoint inhibitor treatment and other immunotherapies has made IDO (along with a similar enzyme, tryptophan-2,3-dioxygenase 2- TDO)  an attractive target for IO drug development, and a variety of  orally available small molecule inhibitors have entered clinical evaluation as both monotherapy and in combination with immunotherapies or cytotoxic cancer drugs.

Big pharma interest in  IDO and TDO inhibitors has fuelled several “big headline” partnering deals, including  BMS and Flexus Biosciences ($1.25 billon); Roche and CuraDev Pharma ($555m); Roche and NewLink Genetics ($1 billion), and Incyte Pharma and Roche, AstraZeneca, Merck and BMS (undisclosed terms).

 

IDO inhibitor progress has been mixed. In June last year, Roche returned the rights to NewLink's navoximod (GDC-0919), the latter failing to meet any of the primary study objectives (overall survival, progression-free survival or objective response rate) when combined with taxane chemotherapy in breast cancer patients.  Combination with Roche's ant-PD-L1 immune checkpoint inhibitor, Tecentriq® did not achieve an overall response rate better than Tecentriq® alone in patients with advanced solid tumours. Absence of efficacy was cited by iTeos Therapeutics today as the reason for termination of an IDO development partnership with Pfizer following analysis of interim trial data from a Phase I monotherapy study in patients with malignant glioma.

Failure in cancer drug development is, unfortunately, the norm rather than the exception, and it's possible that other IDO inhibitors with different chemistries and better bioavailability may prove capable of either upping the response to immune checkpoint inhibitors or being valuable treatments in their own right. Phase II data from a study of Incyte's epacadostat in combination with anti-PD-1 (Keytruda®) hinted that the combination might prove superior to, and safer than, combined anti-CTLA-4 (Yervoy®) and anti-PD-1 therapy in patients with advanced melanoma. A Phase III study (NCT02752074) is underway in collaboration with Merck, with primary data anticipated around the middle of 2018.

AstraZeneca, a company which could stand some good IO related news, recently expanded its collaboration with  Incyte to include lung cancer studies in combination with the anti-PD-L1 checkpoint inhibitor, Imfinzi®; other companies, including Kyowa Kirin, Jubilant Biosys, Kyn Therapeutics and e-Therapeutics have recently entered the IDO/TDO inhibitor game.

The apparent failure of ITeos's  candidate might not give immediate cause for concern (glioma is a very hard target), but it's reasonable to suppose that there are many fingers crossed in pharma management meetings in the hope that Incyte's Phase III study leads to registration and paves the way for the first small molecule IO treatments.

Photo credit: National Cancer Institute

Innate Possibilities

Might modulation of the innate immune
 response turn up the heat on "cold" tumours?

It's been (another) good year for cancer immunotherapy, marked by approval of the first autologous T cell therapies for otherwise untreatable haematological cancers, additional label indications for immune checkpoint inhibitors and even glimmers of hope around personalized cancer vaccines.

All of these advances exploit adaptive immunity- the body's capacity to recognise tumours (and invading pathogens) as "not self" and to programme the immune system to bring exquisitely specific antibodies and effector cells into the attack. A downside to this biological sophistication is that mounting an adaptive immune response takes time and can be deliberately misdirected. We rely on a more primitive and less selective innate immune response as a first defence against rapidly multiplying bacteria and viruses and to prime adaptive immunity.

Bringing the innate immune response into play as a means of increasing the efficacy of cancer immunotherapy is attractive. Non-responsiveness to immune checkpoint inhibitor therapy appears to correlate with tumour inflammation, rather than with immune checkpoint expression or the degree of tumour mutation. Turning “cold” (uninflamed) tumours “hot” (inflamed) might offer patients initially refractory to immunotherapy an additional treatment option.

A signature of tumour inflammation is the presence of IFN-β, a potent cytokine, the production of which is  triggered by STING ("stimulator of interferon genes") in response to molecules ("cyclic dinucleotides"- CDNs) that signal the presence of pathogen or host double-stranded DNA. CDNs produced in response to double-stranded DNA leaking from cancer cells are capable of activating STING and triggering IFN-β production, which in turn, stimulates cancer antigen-specific T cells.

STING activation has attracted the attention of Merck and BMS, rivals in the immune checkpoint inhibitor space. Two investigational STING activators (MK-1454: Merck and ADU-S100: Aduro Biotech/Novartis) are in early clinical evaluation. Both are synthetic CDNs, designed to be more potent than "natural" CDNs but, due to their chemistry, must be delivered directly into the tumour. Spring Bank Pharmaceuticals, BMS (through the acquisition of IFM Therapeutics), iTeos Therapeutics, Invivogen and GSK are also pursuing intratumoral CDN candidates, while Nimbus Therapeutics and CuraDev Pharma are developing small molecules that may allow oral dosing.

Other components of the innate immune system are of interest to immunotherapy developers.  "Toll-like receptors" (TLRs) recognise an array of bacterial and viral debris and are known to be expressed by various cancers. Past clinical studies with TLR-directed agents have been largely disappointing, although a TLR9 agonist, IMO-2125, developed by Idera Pharmaceuticals is under evaluation in combination with immune checkpoint inhibitors in melanoma patients who have previously failed immunotherapy.

"RIG 1 (retinoic acid inducible gene)-like receptors" (RLRs) sense viral infection and can eliminate infected cells, opening the possibility that RLR activation might be exploited to directly kill cancers. RLRs are largely activated by RNA and while perhaps not easily druggable, they offer a promising enough prospect for Merck to have acquired Rigontec, a pioneer in RLR research, for a headline figure of over $500 million.

Inflammasomes are multiprotein complexes of signalling molecules and enzymes that initiate and maintain inflammatory processes in infection and autoimmune disease. Inflammasomes are activated by various "NOD-like receptors" (NLRs), the most widely studied being NLRP3, a trigger sensitive to a wide range of microbial and "damage-associated" molecules, also environmental irritants (silica, asbestos) and amyloid-β, the hallmark protein of Alzheimer's disease. NLRP3 activation may prove to be a practical means of warming up cold tumours and BMS has ambitions to begin clinical studies with an NLRP3 activator in the next 12 months.

Inflammasome activation may not be without risk, being associated with both tumour promotion and suppression in different cancers. Certain tumour-expressed TLRs appears to contribute to development of a benign tumour microenvironment and promotion of metastasis and the STING signalling pathway can contribute to tumour development.  

"Pro-inflammatory" drug development faces the general challenge of achieving an effective degree of tumour inflammation without provoking potentially life-threatening "cytokine storms" or autoimmune adverse events. A better understanding of how the innate immune response might be modulated through the targeting of STING, TLRs, RLRs, inflammasomes or other elements could conceivably lead to novel or improved treatments for a spectrum of conditions that have chronic inflammation at the heart of their pathology. 

Photo credit: Rawich at FreeDigitalPhotos.net

Yet more on bugs and cancer

T-cells (red) on the attack

A Research Highlights piece in December’s Nature Reviews Cancer reports on another intriguing aspect of the interplay between our immune systems and the bugs we carry, namely how gut flora might influence the effectiveness of cancer immunotherapy.

Two international research groups set out to determine  whether the composition of the gut microbiome might influence the response to immunotherapy  directed against  PD-1, a so-called “immune checkpoint “ expressed by activated T cells and macrophages and which is exploited by cancer cells to switch off immune attack. Antibody-mediated blockade of the interaction between PD-1 and its ligand, PD-L1 can restore the anti-cancer response. The anti-PD-1 antibodies pembrolizumab and nivolumab (Opdivo® and Keytruda®, respectively) have proved their worth in the treatment of metastatic melanoma and a variety of other solid tumours.

Genetic analysis of faecal bacteria collected from cancer patients before and after anti-PD-1 immunotherapy found a correlation between gut bacteria diversity and the duration of progression-free survival in cancer patient after treatment.

A collaboration between US and French researchers found differences in the abundance of certain gut bacteria, with Faecalibacterium being enriched in melanoma patients responsive to anti‑PD1 therapy: Bacteroidales was enriched in those patients not responsive to immunotherapy. Differences were also found between responders and non-responders in regards to bacterial metabolism and the composition of immune cells found in the tumour microenvironment. Tumour-infiltrating “killer” T cells were more likely to be found in patients carrying an abundance of Faecalibacterium, while  immunosuppresive cells were more common in individuals carrying abundant Bacteroidales.

Another (again, predominantly American and French) research group found that the abundance of the gut bacterium Akkermansia muciniphila in non-small cell lung cancer and renal cancer patients correlated with a positive response to anti-PD-1 immunotherapy.

Both groups looked for possible mechanistic links between gut bacteria abundance and treatment response. When patient-derived gut bacteria were transplanted into germ-free mice, a variety of favourable effects on tumour growth and immune response were observed, including higher numbers of killer T-cells  and other, immune effector cells, along with changes in the expression of  T- cell receptors for key immune signalling molecules (“chemokines”).

The response to immunotherapy is difficult to predict and involves a variety of tumour factors (PD-L1 expression, tumour burden, degree of mutation) and host factors (immune system genetic makeup, T cell infiltration of the tumour). Analysis of the gut microbiome is unlikely to improve prediction of response, but preservation or manipulation of the gut microbiome through avoidance of antibiotic treatment prior to immunotherapy, or probiotic treatment to encourage “good” bacteria could conceivably translate into better and more sustainable response rates for at least some individuals.  

Photo credit : Rita Elena Serda.  National Cancer Institute \ Duncan Comprehensive Cancer Center at Baylor College of Medicine

CAR-T: A wheel falls off, but still rolling

In the same week that Kite Pharma announced positive data from a pivotal study of its lead CAR-T candidate, KTE-C19 (easier to remember- and to spell- than the non-proprietary designation axicabtagene ciloleucel) in patients with B-cell non-Hodgkin lymphoma (NHL) refractory to other treatments, a one-time leader in the CAR-T race, Juno Therapeutics, pulled the plug on its lead candidate, JCAR015.

CAR-T (chimeric antigen receptor – the “T” is for T cell) is a form of adoptive cell transfer therapy which involves collection of T-cells from the patient and genetically engineering them to express receptors specific for a protein expressed on the tumour surface. After expansion in the laboratory, the transformed cells are infused back into the patient to seek and destroy tumour cells.

CAR-T therapy first made headlines by achieving unprecedented remission rates in patients with acute lymphoblastic leukaemia (ALL), chronic lymphocytic leukaemia (CLL) and NHL where all available treatments had failed to slow disease progression. The other side of the coin was the accompanying high incidence of life-threatening adverse events arising from the massive release of cytokines (part and parcel of the anti-tumour response) and from immune-related neurotoxicity.

Juno’s JCAR015 was placed on clinical hold early in development following a death attributed to cytokine release syndrome and again twice in 2016 following five deaths from cerebral oedema during a Phase II study in ALL patients.  The company initially speculated that the deaths might be related to changes in a pre-treatment regimen involving two chemotherapy drugs but the decision to halt further development suggests that JCAR015 itself is now thought be the culprit. 

CAR-T candidates from Kite Pharma and Novartis have also resulted in high rates of cytokine release and neurotoxicity-related adverse events, but, so far, these have proved to be more manageable or of lesser severity than those occurring during the JCAR015 studies. No cerebral oedema occurred in the Kite Pharma pivotal study, with two treatment-related deaths probably arising from cytokine release.

Juno hope to stay in the game with an earlier stage CAR-T candidate, JCAR017, which showed a relatively low incidence of severe adverse events  in a small study conducted in NHL patients, but the abandonment of JCAR015 puts Juno a long way behind Kite Pharma and Novartis, with both shooting for regulatory approval in 2017.

CAR-T treatment will probably never be a “safe” option, although adverse event management would be expected to improve with experience. If regulators can be convinced that the benefits of CAR-T therapy outweigh risk, safety is likely to be a secondary concern for individuals cursed with otherwise untreatable B-cell malignancies. 

An arguably bigger challenge facing Kite Pharma, Novartis and other CAR-T contenders is whether individualised adoptive cell transfer therapies can be reliably scaled up and delivered at a cost that healthcare systems are able and willing to meet.

---

Kite Announces Positive Topline Primary Results of Axicabtagene Ciloleucel from First Pivotal CAR-T Trial in Patients with Aggressive Non-Hodgkin Lymphoma. Company press release online 28^th February 2017. http://tinyurl.com/js7293j

Juno Therapeutics Reports Fourth Quarter and 2016 Financial Results. Company press release online 1^st March 2017. http://tinyurl.com/hunp9uh

ASCO 2017 Annual Report again picks immunotherapy as “Advance of the Year “

ASCO, the American Society of Clinical Oncology, is probably best known to followers of the pharma and biotech industries for its high profile annual conference, always the subject of intense sector analyst scrutiny.  ASCO also publishes a highly-readable annual report highlighting clinical advances in cancer therapy and the shape of future research.

Once again, immunotherapy (dubbed “Immunotherapy 2.0” by ASCO) takes the honours as “Advance of the Year”, underscoring the breakthrough nature of this approach to cancer treatment and its expanding role across a growing number of cancer indications.

Put very simply, immunotherapy utilises the patient’s own immune system to combat cancer. Tumours thrive by deploying a variety of countermeasures which are highly effective in subverting the immune response.  A mechanism common to several tumour types is surface expression of proteins that lock onto receptors (“immune checkpoints”) present on T cells,  resulting in their deactivation. By deliberately blocking this interaction, T-cell “seek and destroy” functions can be restored.

Immune checkpoint inhibitors were first approved on the basis of their efficacy in metastatic melanoma, with the first being Yervoy® (ipilimumab: Bristol Myers Squibb) in 2011, followed by Keytruda® (pembrolizumab: Merck) and Opdivo® (nivolumab: Bristol Myers Squibb) in 2014 and,  most recently, Tecentriq® (atezolizumab: Roche) for the treatment of some forms of lung cancer. A number of other biologic immune checkpoint inhibitors are in late stage clinical evaluation.

From the outset, checkpoint inhibitor treatment has been notable for impressive increases in patient survival, although not across the board. Reliable identification of those patients most likely to benefit from checkpoint inhibitor therapy remains a frustration. Optimum duration of therapy also remains to be established. Given the cost of checkpoint inhibitor treatment (around £30,000 before an undisclosed discount in the UK and around $150,000 in the US), patient selection and length of treatment are of key importance to healthcare systems already struggling with soaring cancer therapy expenditure.

Recent checkpoint inhibitor approvals include treatment of head and neck, bladder and renal cancers and Hodgkin’s lymphoma, and evaluation is progressing in liver, breast, gastric and other cancers. The need to attain market dominance is a major driver of clinical trial activity: at the end of 2016, Merck’s Keytruda® was being trialled against 30 tumour type in more than 350 registered studies, of which around 100 studies will evaluate treatment combinations.

Hundreds of micro and mid-cap companies are looking to stake a claim in the immunotherapy (aka “immuno-oncology) space. Some are hopeful that repurposed drugs can modify the tumour microenvironment to favour the immune system, while others believe that combination with checkpoint inhibitors and other agents can boost the so far disappointing efficacy of cancer vaccines.

Tumour immunology remains poorly understood. Potential big winners in next generation immunotherapy are those companies engaged in the unravelling of tumour defence mechanisms to find exploitable vulnerabilities.

Who knows, but given the rate of progress, the 2027 ASCO “Advance of the Year” could well be “Immunotherapy 12.0”.

---

ASCO 12^th Annual Report on Progress Against Cancer. 2017 Clinical Advances. Online 1^st February 2017    http://tinyurl.com/zwzv5vg