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Vaccines

Anti-Telomerase Vaccines

Date: April 10, 2003

by Chaya Venkat

Geron's Phase I Trial

injections

We recently examined an interesting report on Geron Corporation's Phase I clinical trial results for prostate cancer using an anti-telomerase vaccine approach. This is clearly an important approach to what could potentially be termed "universal cancer vaccine" that would hopefully work for a variety of cancer types. Before we can discuss how anti-telomerase cancer vaccines may work, it might help to have an overview of "telomeres", our internal clocks that control how our very cells age and die.

Overview of Telomeres / Telomerase

Each cell in your body has 46 chromosomes, 23 of them come from your mother and 23 from your father. In the normal process of living, cells die and are replaced by new cells. Every time a cell divides in two to make two new cells, the 46 chromosomes in the original "mother" cell are exactly duplicated in the new daughter cells. Well, not exactly, the problem is that when a chromosome is duplicated, the Xeroxing process does not happen exactly right to the very tips. This is where the "telomeres" come in: these are little caps at the ends of each strand of chromosomes. 46 chromosomes per cell, which means there are 92 telomeres, two each per chromosome, to cap the two ends of the chromosome, keep a lid on things as it were.

Think of it this way: each of the laces on your sneakers is a chromosome, and the little plastic tips at each end is a telomere. Those plastic tips are important, without these tips to protect them, the laces will soon fray and decay. The telomeres keep the genetic information of the chromosomes intact, without getting frayed and corrupted from one generation of mother cells to the next generation of daughter cells. Since the telomeres themselves carry no genetic information, the fact that the very tips are not duplicated exactly makes no difference.

In fact, the length of the telomere gets shortened with each duplication. In every generation, the daughter cells have slightly shorter telomeres than their mother cells had, because a little bit of the telomere at the very tip does not get duplicated. When the telomere gets worn down to a nub and finally disappears after a defined number of cell divisions, it is no longer possible for that cell to divide properly any more. The cell has aged to a point where it is no longer viable, and dies. Think of this as an aging process, at the very cellular level, a built-in mechanism for getting rid of old cells that have been through too many cell divisions and no good any more.

This is actually an important mechanism that the body has developed, to avoid premature cancer. Using an analogy that is more or less accurate, if you Xerox a document, then Xerox the copy once more, keep doing this for many times, each time copying the prior generation copy, you can imagine that after a while the copies will start looking blurred, smudged and no where as clean and clear as the original document. There will be a gradual accumulation of spots, smudges and errors, to the point where the document is no longer readable. Same thing with cells. As time goes one, there is a gradual process of accumulation of genetic misinformation in the chromosomes, and particular errors in a given chromosome in a given cell are dutifully passed on to its daughters. As in our Xerox analogy, errors continue to accumulate over many generations, to the point where the cell is no longer a well functioning cell. It is no longer desirable for this defective cell to reproduce and make more daughters and grand daughters of itself. This is where the gradually shortening telomeres come in, to deliver the kiss of death, and the cell dies with no further reproduction. It is believed that shortened telomeres and eventual death of cells that have gone through their ordained number of divisions may be responsible for some of the changes we associate with normal aging.

There are one particular bunch of cells in your body, that are exempt from the telomere control of how many times they can divide: these are the reproductive cells, the eggs and the sperm. Makes sense, if the species is to continue, babies must get born based on a single fertilized egg, and this single cell then goes on to make a whole human being. There is a particular enzyme, called "telomerase" that has been called an immortalizing enzyme. It has the capability of adding to the length of the telomere tips after each cell division, keeping intact the length of the tips, compensating for the erosion of the tips that would happen with each cell division, in the absence of the activity of this enzyme. Without telomerase activity to counteract the effect of the shrinking lengths of telomeres on reproductive cells, the human race will become extinct very soon.

Besides the reproductive cells, the enzyme telomerase is expressed also in proliferative cells of renewal tissues (e.g. bone marrow cells, basal cells of the epidermis, proliferative endometrium, and intestinal crypt cells). It is not expressed and it is undetectable in normal cells. Now comes the punch line, it has been found that most human tumors have high telomerase activity while most normal human cells do not, with the exceptions noted above. Telomerase activity in cancer cells means that the "immortalizing enzyme" is working in these malignant cells, keeping the telomeres from getting shorter with each generation. Such malignant cells can keep dividing indefinitely, producing more and more corrupt copies of themselves. It has been proposed that up-regulation of telomerase and its activity may be a critical event responsible for continuous tumor cell growth.

Most, but not necessarily all, malignant tumors may need telomerase to sustain their growth. This up-regulation of telomerase activity may be a necessary step required for the continuing proliferation of advanced cancers. There is experimental evidence from many researchers that telomerase activity is present in almost all human tumors but not in normal cells that may be right next to the tumor. Telomerase researchers are working on using this fact to develop ac curate and quick methods for detecting cancer in the first place, by looking for the tell-tale signals of telomerase activity; and next step, control the explosive proliferative growth of cancer cells by taking away their immortalizing enzyme.

There is a lot of information available on this subject, I have sampled a few abstracts below to give you a sense of the type of work that is going on, specially in the context of CLL. The first two PubMed citations below discuss telomere length and telomerase activity in the context of CLL patient survival prognosis. The authors conclude, "telomerase activity was the most significant prognostic factor for overall survival in B-CLL". Both of these papers link short telomeres with increased telomerase activity, and poorer prognosis.

Once we start discussing CLL prognostic indicators, can IgVH gene mutation status be far behind? The third PubMed citation connects the dots: short telomeres, high telomerase activity and unmutated IgVH gene status all go together, and this may explain why the patients with unmutated IgVH gene have a poorer prognosis, they are also the ones with high telomerase activity in their CLL cells, making them "immortal".

So much for understanding telomeres and telomerase activity, and how this can possibly be a good prognostic tool for cancers of all kinds, including CLL. So what can be done about it? This is where the Geron technology comes in. Researchers at Duke and Geron came up with a technique where by bits of telomerase are fed to mature dendritic cells obtained from the patient, by leukapheresis of blood. This brew is then injected back into the patient as a vaccine. As you know by now, dendritic cells are very good at presenting bits of proteins to "effector" cells such as T-cells. When snippets of telomerase are presented as antigens by these professional antigen presenting cells (APCs), T-cells are activated to become killers, going after any cell that displays the protein fragments that had been defined as antigens by the APCs. The Duke clinical trial showed that in the vast majority of patients, after vaccination with appropriately indoctrinated dendritic cells, such an activation of T-cells to become Cytotoxic T-Lymphocytes (CTLs) did indeed happen, and there was a decrease in circulating prostate cancer cells in the blood. They also observed no toxicity or side effects attributable to the vaccination.

So far, so good. I guess the big question for us folks is how long it is going to take from Phase-I clinical trials for prostate cancer to go to late stage trials for CLL. This waiting game can be hard on patients' nerves, especially those facing therapy decisions in real time.

Telomerase Assembly Line

Reference:

Link: Geron Corp publications on telomeres and telomerase.

Abstracts:

Cancer Res 1998 Nov 1;58(21):4918-22

Telomere length and telomerase activity predict survival in patients with B cell chronic lymphocytic leukemia.

Bechter OE, Eisterer W, Pall G, Hilbe W, Kuhr T, Thaler J.

Department of General Internal Medicine, Innsbruck University Hospital, Austria.

The telomere-telomerase hypothesis states that the vast majority of human tumors have a prolonged replicative life span throughout expressing telomerase, which compensates the cell division-associated loss of telomere DNA. The use of telomere length and telomerase expression as new biological markers in cancer patients requires their correlation with disease prognosis. We, therefore, correlated the mean telomere length based on a telomere restriction fragment assay and the activity of telomerase measured with a telomeric repeat amplification protocol with clinical data and overall survival in 58 patients with B cell chronic lymphocytic leukemia (B-CLL). Telomere length showed a highly inverse correlation to telomerase activity. Patients with telomeres below 6.0 kb were associated with high telomerase activity, whereas patients with a telomere length >6.0 kb generally showed low enzyme activity (P <0.001). Patients in Binet A exhibited significantly longer telomeres and had less telomerase activity than did patients in Binet B or Binet C, where significantly shorter telomeres and higher telomerase activity were observed (P=0.031). Short telomere length and high telomerase activity were significantly associated with a shorter median survival (P=0.02 and P <0.001), and telomerase activity was the most significant prognostic factor for overall survival in B-CLL (P <0.001). Our data provide evidence that telomere length, as well telomerase activity, exerts a strong impact on the survival of B-CLL patients and that telomerase activity can be used as a new prognostic marker in this disease.

PMID: 9810000
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Br J Haematol 1999 Sep;106(3):662-8

Telomerase activity in chronic lymphoproliferative disorders of B-cell lineage.

Trentin L, Ballon G, Ometto L, Perin A, Basso U, Chieco-Bianchi L, Semenzato G, De Rossi A.

Department of Clinical and Experimental Medicine, Clinical Immunology Branch, University School of Medicine, Padova, Italy.

The progressive shortening of telomeres at each cell division is a key mechanism in controlling cell proliferative capacity. The activation of telomerase, a reverse transcriptase that extends telomere length, potentially leads to unlimited cell proliferation, and is believed to play a critical role in the neoplastic process. High levels of telomerase activity have been demonstrated in almost all solid tumours; however, little data is available concerning its expression in chronic B-cell neoplasms. By using a quantitative polymerase chain reaction-based method we quantified telomerase activity in normal B lymphocytes, and in various B-cell malignancies, including chronic lymphocytic leukaemia (CLL), mantle cell lymphoma (MCL) and hairy cell leukaemia (HCL). Compared to normal B cells, which expressed very low levels of telomerase activity, malignant cells from most of the patients showed a significant increase in telomerase activity, with highest values observed in HCL samples. Moreover, among the CLL and HCL cases, significantly higher levels of telomerase activity were found in patients with progressive disease at 1 year follow-up versus patients with stable disease. These data suggest that telomerase activity might correlate with disease progression.

PMID: 10468854
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Br J Cancer 2003 Feb 24;88(4):593-8

Association between telomere length and V(H) gene mutation status in chronic lymphocytic leukaemia: clinical and biological implications.

Hultdin M, Rosenquist R, Thunberg U, Tobin G, Norrback KF, Johnson A, Sundstrom C, Roos G.

Department of Medical Biosciences, Pathology, Umea University, Sweden.

The immunoglobulin V(H) gene mutation status can divide B-cell chronic lymphocytic leukaemia (CLL) into two entities with a different clinical course. Cases with unmutated V(H) genes, considered to evolve from pregerminal centre (GC) cells, have a worse outcome compared to cases showing mutated V(H) genes, that is, post-GC derived. Also, telomere length has been reported to be of prognostic s ignificance in CLL. Interestingly, telomerase becomes activated during the GC reaction and an elongation of the telomeres occurs in GC B cells. We performed telomere length and V(H) gene analysis in a series of 61 CLL cases, in order to investigate if the unique telomere lengthening shown in GC B cells could reflect the telomere status in the two subsets of mutated and unmutated CLL. A novel association was found between V(H) gene mutation status and telomere length, since significantly shorter telomeres were demonstrated in the unmutated group compared to the mutated group (mean length 4.3 vs 6.3 kbp). Shorter telomeres also constituted a subgroup with a worse prognosis than cases with longer telomeres (median survival 59 vs 159 months). Furthermore, the Ig gene sequence data revealed that samples with high mutations frequency (>6%) had long telomeres ( approximately 8 kbp). Thus, both the telomere and V(H) gene mutation status in CLL appear linked, which may reflect the proliferative history of the clonal cells with regard to the GC reaction.

PMID: 12592375
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