Tuesday, December 20, 2011

Deploying Immunotherapeutic Drones for Cancer

Nearly six scores ago, a Westfield, Connecticut, based bone surgeon, William Coley, injected a mixture of dead Streptococcus pyrogens and dead Serratia marcescens bacteria (called Coley's vaccine or Coley's toxins) in patients' tumors and obtained a near-complete remission.  Nearly a quarter century after his death, the powerful immune stimulant in Coley's vaccine was identified as tumor necrosis factor-alpha (TNF-α) in 1968.  Today, there is a renewed interest in Coley's approach and the immunotherapeutic strategies to control cancer.

Unleashing the power of immune system on the rogue cancer cells has a particular appeal over classical cytotoxic chemotherapy or modern targeted therapies because of the promise of long-term durable response.  The enthusiasm, however, has been tempered by the excruciatingly slow progress in the clinical development of immunotherapeutics and many roadkills already on the clinical trial highway.  

Until recently, there were only a handful of anti-cancer immunotherapeutic agents in routine use:
  • High-dose IL-2 infusion
  • Interferon-alpha for renal cell carcinoma and high risk melanoma
  • BCG (bacille Calmette-Guerin) vaccine instillation in the bladders of patients with urothelial carcinoma of the bladder.

However, with the FDA approval of several new immunotherapeutic agents, the tide is finally turning.  These recently approved agents are:  

  • Protein-subunit based vaccines, Gardasil (Merck) and Cervarix (GlaxoSmithKline) for the prevention of HPV-driven cancers, including, cervical, anal, vulvar, vaginal and some throat (head and neck) cancers;
  •  a dendritic cell-based vaccine, sipuleucel-T (Provenge; Dendreon) for advanced prostate cancer (CaP); and 
  •  a human monoclonal antibody targeting CTLA-4 cytokine, ipilimumab (Yervoy; Bristol-Meyers Squibb) for metastatic melanoma.

A notable observation about these approved drugs is that they cover multiple immunotherapeutic approaches.  While approval of these drugs is a cause for optimism, there are serious, but not insurmountable hurdles ahead.  In the August 2011 issue of Nature Reviews Drug Discovery is an article by Cornelis J. A. Punt and colleagues from The Netherlands, Cancer Immunotherapy--revisited.  In this article, Cornelis lists following reasons that have hamstrung clinical development of cancer immunotherapeutics
  1. Difficult to define optimal does and schedule for immunotherapies.  Cornelis gave an example of KRN7000 whose development was abandoned.  A Natural Killer T-cell (NK T-cell) activator, KRN7000 (α-galactosylceramide (αGelCer); Kirin Brewery Co., Ltd.) was tested in the Phase I trials with a dose-escalations of two logs (96-fold from 50mcg per sq m to 4.8 mg per sq m); it failed to show objective response, correlation with dose, but had no toxicity.  This was in contrast to its potent antitumor activity in various animal models.  While clinical development appears to have been dropped, research on this compound, however, continues (eg. PMID218657168866665).  Similarly, there is a tale of two anti-CTLA-4 targeting drugs, iplilimumab and tremelimumab.  Ipilimumab which was tested at a monthly dosing schedule in metastatic melanoma showed clinical benefit.  On the other hand, tremelimumab which was tested at a every 3 month dosing schedule, failed in the Phase III trial.  There may be other reasons for tremelimumab failure, but dosing schedule can not be overlooked.
  2. Choice of target patient population.  Many vaccine approaches work best in patients with early cancer, low tumor burden and with microscopic disease.  Yet, clinical trials are often (ethically and practically) geared towards those who have advanced end-stage disease, the patient subset unlikely to respond.
  3. The traditional endpoint criteria defined by WHO and RECIST (Response Evaluation Criteria In Solid Tumors) are inadequate for evaluation of patient response to immunotherapies.  RECIST criteria uses tumor size, and volumetric decrease or increase of tumor to define the efficaciousness or failure of a chemotherapeutic drug, respectively.  Patients treated with Immunotherapeutic drugs often exhibit an initial progression of the disease (even spawning new lesions) before the disease regression occurs:  Some ipilimumab treated melanoma patients had shown an increase in new tumors or metastasis; however, the tumors then regressed.
  4. The non-RECIST dynamics complicates the design of clinical trials.  The planned interim analysis are definite pitfalls which may led to premature termination of clinical development of an otherwise promising drug.
  5. The surrogate endpoints and tools are not standardized.  Consistent read-out methods are required.  MIATA (Minimal Information About T cell Assays) project by US and European consortium aims to standardize the reporting of common T cell assays, such as, ELIspot, intracellular cytokine assays and MHC tetramer assays.  The current guidelines are available at MIATA website.  Another suggestion in Cornelis' review is the monitoring of immune response at tumor site in addition to peripheral blood.
  6. Patenting issues hinder availability of funding.  It is easy to patent small novel molecules than immno-strategies because parts of the protocol may be controlled by other patent-holders requiring cross-licencing negotiations.
  7. Pharma's clinical development schedule may be unwise.  Sometimes, the clinical development proceeds in the absence of robust translational research.  For example, a host of dentritic cell vaccine trials in melanoma have failed, in part, due to the technology to manufacture vaccine not being commercially ready and at par.  On the other hand, high-dose IL-2 therapy is highly effective for some patients; yet, we still do not have good understanding of its mechanism of action.
  8. Cancer antigens chosen as targets are often self-proteins and are subjected to immune tolerance.  Breaking this tolerance by anti-cancer immunotherapy often invites serious toxicity in the form of autoimmune reactions.

Types of immunotherapeutic strategies:
> Vaccine-based: Peptide, protein, DNA, etc.
> Cell-based vaccines: Dendritic cells and antigen-presenting cells.
> Cytokines and immune-targeted agents.
> Adoptive T cell strategies.
(see a list of startgies in research or development in Joost Lesterhuis et al. review (link below in refs)

Immunotherapy enthusiasts may be taken to the woodshed (and chopped!)

Recently, I posted a link to a Newsweek article, Could This Be The End Of Cancer?, by Sharon Begley at a LinkedIn discussion group.  I received a few emails, some dismissing the headline as "tabloid" and others pointing to the dismal record of immunotherapeutic strategies.  All these people have missed the central theme of this article, and probably did not read the whole article and readers' comments below the article!  It's an article on optimism and as she writes,
“ 'Could' is the key word. Cancer vaccines are still being tested. Patients, doctors, and scientists know only too well that seemingly wondrous cancer therapies can flame out."
Sharon Begley starts with the story of Shari Baker, who at age 53 was diagnosed with Stage IV (i.e., metastatic) breast cancer, and faced the grim statistics: Stage IV breast cancer claims the lives of 80% of the patients within five years.  Shari Baker was able to beat these odds (and is alive today) because she was part of a clinical trial testing HER-2/neu vaccine.  Today, this vaccine based on peptide fragments of HER-2/neu protein which is over-expressed in breast cancer is in Phase II trials (clinicaltrials.gov link).  Sharon also points to other successes.  Provenge, first ever FDA-approved cancer vaccine for prostate cancer [...].  Provenge is a dendritic-cell based vaccine tailormade for each patient.  Many more dentritic cell vaccine are in development for other cancers [...].  NCI has seen initial positive results with PANVAC vaccine in ovarian and pancreatic cancer patients.  PANCVAC contains CEA and MUC1 antigens which are overexpressed in ovarian and pancreatic cancers.  These peptide vaccine stimulate Killer T cells to target antigen-tagged tumor cells. Biovest International is expected to file for the FDA approval of BiovaxID vaccine in 2012 for treatment of glioblastoma multiforme and follicular lymphoma.  BiovaxID vaccine is based on EGFR variant III protein fragments.  Cimavax-EGF vaccine developed by Cuba Center of Molecular Immunology (CIM) at Havana is being used outside United States for advanced lung cancer [......].  

The greatest advantages of vaccine approach are: Immune system has memory and it can change its arsenal (killer T cells, neutralizing antibodies, etc.) in tune with the changing  colors (antigens) of the tumor cells.   Targeted therapies fail once the tumor cells figure out alternate survival pathways.  Chemo and targeted therapies are good for "shock and awe," but durable response requires the street-fighting capabilities of patient's own immune system.  

However, there are issues and limitations:  some patients are too sick to mount an immune response; immune response may take longer to be effective against metastatic disease; but, the most important is the tumor's ability to evade or suppress patient's immune system.  The recently approved ipilimumab (aka Yervoy) targets and blocks CTLA-4 protein.  CTLA-4 cytokine is a member of a family of proteins involved in dampening the immune system, particularly blocking immune responses against self-antigens.  Knock out the CTLA-4 gene in mice and they die of lymphoproliferative disease (an autoimmune disorder.)  Yervoy at US$120,000 per year which works by breaking the immune-evasion strategy of tumor cell is not ideal, and is associated with a host of immune-related toxicities, including, colitis, dermatitis, hepatitis, thyroiditis and hypophysitis.  Still, it the first treatment in 30 years to show a survival benefit in metastatic melanoma.  There are other immune checkpoint proteins besides CTLA-4.  Targeting PD1, for example, also reactivates tumor-specific Killer T cells.  Anti-PD1 monoclonal antibody which is another candidate drug has an advantage of much less autoimmune toxicity over CTLA-4 targeting ipilimumab.

Steve Jobs and the Immunotherapy Skywalkers

To the naysayers, I have four words, read Steve Jobs biography and they will find themselves totally opposite to people like Steve Jobs.  Had Steve not pushed adamantly for a stylus-free tablet computer at a time when nobody believed it was possible, we would not have seen the iPad revolution today.  Steve Jobs hated the idea of using stylus; he said that the God-given stylus is the finger--and he was right.  This is the lesson for the anti-cancer immunotherapy pessimists and arm-chair analysts out there.  If I may also remind them: 

Cancer is a chameleon beast like HIV and Malaria; all three will need the power of our own immune system to tame.

Further Reading
National Cancer Institute: About Cancer Vaccines and cancer vaccines in clinical trials 

W. Joost Lesterhuis, John B. A. G. Haanen, & Cornelis J. A. Punt (2011). Cancer immunotherapy – revisited Nature Reviews Drug Discovery, 10 (8), 591-600 : PMIDdoi:10.1038/nrd3500 | PDF via Scholar |

Update Dec. 23, 2011
MedImmune In-Licenses Cancer Immunotherapy Tremelimumab from Pfizer (Oct. 3, 2011) -- MedImmune plans to develop tremelimumab (aka CP-675,206), a CTLA-4 monoclonal antibody for use in combination with chemo.

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