Vaccines el pt

A Vaccine Trial for CLL Patients

Date: March 4, 2024

by Chaya Venkat

Finally, It Is Our Turn …

Editor's Note: The Genitope CLL trial has been posted on www.clinicaltrials.gov with the following title:

Phase 1/2 Study to Evaluate the Feasibility and Tolerability of Treatment of Previously Untreated B-CLL.
As of August 2024, this trial had completed its accrual of patients and was closed to new registrants.

More than two years ago, January 2024 to be precise, PC and I were invited to attend an advocacy meeting at the headquarters of Genitope Corp. (For the curious, here is a link to a snapshot taken at the meeting.) Genitope is one of a few companies that has a serious technology with demonstrated potential for developing a vaccine for B-cell cancers. At the time of our meeting with the company, their vaccines were in late stage trials for non-Hodgkin’s lymphoma, particularly for follicular lymphoma. We did our usual song and dance about how this technology needed to be extended to cover CLL patients as well. I am happy to report Genitope is finally ready to launch their vaccine trial for early stage and chemo naïve patients. You can read their Press Release and their MyVax® backgrounder on the Genitope website but their trial-specific FAQ and recruitment announcement have been removed from the corporate website.

There is a lot of art and science to the creation of effective vaccines and all too often there is hype associated with words such as “vaccines” and “gene therapy”. Patients associate these words with high tech medical fixes for what ails them and assume there is no price to pay in terms of risk. I know of several patients who waited too long to initiate therapy while waiting for the “Star Trek” equivalent of a “ gene therapy cure”, and paid the price of ending up with advanced disease that was subsequently harder to treat. The Genitope technology has real merit, if the results from the NHL trials are any indication. For a segment of our patient community this may be a very interesting option indeed. As always, the devil is in the detail. For starters, if this clinical trial is of personal interest to you, it is important you understand how this vaccine is supposed to work. I strongly urge you read our earlier article describing the technology: An Idiotype Vaccine for CLL?. The present article will deal with a review of the actual design of the Genitope clinical trial and consider the pros and cons.

Summary of Idiotype Cancer Vaccine Technology

By now you are familiar with the word “clonal” in describing CLL. What this means is that all of the CLL cells in your body are duplicate copies of each other, clones grown from the first cell that went bad and became the patriarch of all the descendent CLL cells that grew out of it. Each CLL patient has a unique clonal population of CLL cells, with its own unique ‘fingerprint’ — and this fingerprint is subtly different for each patient. (This is a bit of oversimplification, but adequate for our purposes in this article). One of the unique markers carried by each CLL cell in your body is the surface immunoglobulin. Each CLL cell has several copies of the same unique immunoglobulin marker sprouting on the surface of the cell. Cancers such as follicular lymphoma carry literally thousands of these signature immunoglobulin markers on each cancer cell. CLL patients, on the other hand, have a mere handful of immunoglobulin markers on each cell — you will see this as “dim” expression of surface Ig in your flow cytometry report. This is an important difference, as you will see below. The jargon for the characteristic and unique nature of the surface immunoglobulin is “idiotype” (“Id” for short) and the vaccines made using this and other similarly unique markers are called “Idiotype vaccines”.

As in the case of the vaccines used in NHL trials, the Genitope vaccines for CLL patients are custom made for each patient. A sample of your particular cancer cells are obtained from your blood. Using a complex and proprietary process, the unique Ig of your particular version of CLL is isolated, expanded, and protein fragments of this Ig are then used as the vaccine. In an effort to make the vaccine more potent, it is combined with “KLH”, a Hemocyanin protein fragment from Keyhole Limpets, a type of giant sea mollusk that lives off of the coast of California. This KLH fragment appears so weird and bizarre to our mammalian bodies that it gets a strong immune reaction, something to be desired when we are trying to get a robust response to vaccine administration. Another adjuvant that is given along with the vaccine is GM-CSF (Granulocyte Macrophage Colony Stimulating Factor, trade name “Leukine”). The idea is to increase the production of neutrophils and macrophages, since these are the cells that will eventually do the killing of the cancer cells. It is a bit like deputizing a lot more officers when there is a man-hunt underway.

CLL Vaccines: Pros and Cons

Vaccine approaches have some built-in advantages. Getting your own immune system to become aware of infected cells and able to identify and kill them when they are spotted, this has some real advantages. Vaccination techniques have been used with great effectiveness in dealing with viral infections, such as smallpox, polio, even the annual flu. Unlike “foreign” drugs that can cause unwanted side effects, chances are vaccines that goose your own immune system to be more efficient are going to be better tolerated. This is a bit of a generalization — some people may have allergic reactions to one or more of the components of the vaccine. But by and large, vaccinations have saved millions of babies from polio and whooping cough and have all but eradicated deadly diseases such as smallpox.

But there is a big difference between pre-emptive administration of vaccines ahead of infection in healthy people and vaccination after the fact in cancer patients. Getting a well-disciplined, well-funded and beefed up police force trained and on the look out for the bad guys is an effective strategy. But if you are dealing with a town that is already overrun by bandits, where the police force is out-gunned, under-powered, and demoralized, that is an entirely different kettle of fish. CLL patients fall into the second category. You already have a well established and thriving population of cancer cells in your body. And the kicker is that CLL is a cancer of an arm of the very immune system that is needed to mount an immune response to the cancer, a little bit like the police department riddled with bad cops. Not only are the B-cells (the “humoral” arm of the immune defenses) compromised by B-cell CLL, it is now pretty well established that CLL interferes with the proper function of the other arms of the immune system (the “cellular” arms) that are necessary in proper response to vaccination. Dendritic cells and T-cells are thought to be “anergic” or demoralized as a consequence of CLL. This is one reason why even the annual flu vaccinations are less effective in CLL patients.

Then there is the problem of out-numbered armies. There may be just way too many bad guys (CLL cells), compared to the good cops (good immune system cells) that can be mustered. This is the reason why most vaccine therapies in cancer patients are attempted when the tumor load is low and in combination with immune boosting GM-CSF as an adjuvant. Despite these hurdles, encouraging results are being seen in late stage trials of vaccines in B-cell cancers, mostly in lymphomas up to this point. Note the lack of any significant toxicity in these large trials, a major point in favor of vaccine approaches.

Abstract:

Curr Opin Oncol. 2024 Sep;17(5):432-40.

Current status of therapeutic vaccines for non-Hodgkin's lymphoma.

Hurvitz SA, Timmerman JM.

Division of Hematology/Oncology, Center for Health Sciences, University of California-Los Angeles, Los Angeles, CA

PURPOSE OF REVIEW: Therapeutic vaccines targeting B cell lymphoma idiotype have reached an advanced stage of clinical development, with three multicenter randomized clinical trials ongoing. This review describes the rationale and development of this immunotherapeutic approach, the design of current phase III trials, and other active vaccination approaches likely to move forward into clinical testing for lymphomas.
RECENT FINDINGS: Several groups have achieved promising results in phase II trials of patient-specific idiotype vaccines, with very few side effects noted. Anti-idiotype antibodies, in addition to cytotoxic T cells, are now believed to be important effectors of antitumor immunity after idiotype vaccination. The manufacturing of autologous tumor idiotype proteins is being rapidly refined by the use of molecular technologies. Two trials involving more than 1000 patients are now under way, which use idiotype vaccination after induction chemotherapy; one trial completed accrual in early 2024. A third trial opened in 2024, using rituximab followed by idiotype vaccine with maintenance booster vaccines continuing throughout the period of normal B cell recovery. In accordance with the United States Food and Drug Administration, progression-free survival serves as the accepted primary efficacy endpoint in these studies.
SUMMARY: Lymphoma idiotype vaccination represents a promising immunotherapeutic approach targeting a patient-specific tumor antigen. The results of pivotal phase III trials for three first-generation idiotype vaccines will become available in the next several years. Advanced manufacturing techniques should permit application of this tailor-made treatment to large numbers of non-Hodgkin's lymphoma patients.

PMID: 16093791
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The Genitope Clinical Trial

Here are the highlights of the trial, along with my comments.

• This trial is open only to untreated and early stage CLL patients (Rai stage 0, 1 and 2). Makes sense: anyone with more advanced stage disease is likely to have too much tumor load and not likely to benefit from the vaccine. You can look up the definitions of the various Rai stages here (Survival and Staging).
• The trial will be offered at a number of locations, but for now the only site open is the UCSD site. (Principal Investigator is Dr. Tom Kipps; contact his nurse Jan Bole at 858-822-2405). My expectation is that it will soon be announced at other centers across the country, at locations that may be accessible to more patients. Since the trial design requires quite a few trips to the trial center for administration of the vaccine and booster shots (16 shots over a period of 1 year!) as well as for general monitoring and testing purposes, it can quickly get quite expensive if you have to travel from one coast to the other. Travel and lodging costs are rarely covered by insurance companies — make sure you have thought through the dollar consequences before you sign up.
• Volunteers must be untreated. This is a departure from prior vaccine designs in follicular lymphoma, where it was required that participants get de-bulking chemotherapy ahead of vaccination. I expect Genitope hopes the early stage of the patients is enough to assure their vaccines do not face insurmountable tumor loads. There is serious concern that the very process of undergoing chemotherapy further damages the immune system, making it less capable of responding to the vaccine. There is some logic to trying vaccines as the frontline therapy in very early stage patients to see if we can nip the problem in the bud before the cancer gets too entrenched.
• In any vaccination approach, there is always the worry that the goosed up immune system will go berserk and start attacking perfectly good cells in the body. This is particularly important in groups such as CLL patients, who are so much more prone to autoimmune diseases of various kinds. Genitope correctly excludes patients who have existing autoimmune disease (AIHA, ITP) or on steroidal medications of any sort.
• Genitope particularly rules out prior therapy with Rituxan. Remember, Rituxan kills all B-cells, both the good B-cells as well as the cancerous CLL cells. B-cells are an important part of the immune system, part of the “humoral” arm. The other arm of the immune system is the “cellular” arm, and T-cells are important here. Genitope feels the humoral response is important in vaccinations, as well as T-cell driven “cellular” response. In this respect Genitope differs from Favrille, Inc., their major competitor. Favrille has just announced a vaccine clinical trial for NHL and SLL patients, where pre-treatment with Rituxan is integral to the process (Favrille clinical trial listing).
• Genitope expects it might take as much as 8 months to make the custom vaccine for each patient. In other words, you need to have a sufficiently indolent version of CLL, so that you can wait it out without any treatment for the (up to) 8 months between when you are accepted into the trial and a sample of your cancer cells are collected, to when the vaccine is ready for use. This is not a trivial point, and I will be discussing this in more detail in the editorial section.

Editorial

Genitope is not the only company that is investigating idiotype vaccines for B-cell cancers. The NCI has its own set of trials and Favrille Inc. has been busy as well with their own large scale phase 3 trials. All of this is good news for us, since a little bit of competition is good for separating the real winners from the also-ran technologies. My friend Karl of Patients Against Lymphoma has published an excellent comparison of the different technologies, the pros and cons of each technology and the results obtained thus far. I urge you to browse through this on his site, here is the link: Vaccine Comparison on Lymphomation.org.

I am delighted that Genitope has finally extended their technology to include CLL patients. As they say, better late than never. The recently announced Favrille vaccine clinical trial says “SLL” patients are included, but I am told that in this case “CLL” is not the same as “SLL”. If your diagnosis lists you as SLL/CLL patient, you may have wiggle room to see if you are eligible for the Favrille trial as well. This may be of particular significance if you need therapy for reducing tumor load prior to vaccination, since Favrille includes Rituxan therapy ahead of vaccination as integral part of their clinical trial. I am trying to establish contact with this company — and if I get any additional information I will report back to you.

The inclusion criteria of the Genitope trial limit participation to a narrow segment of our patient community. You must be early stage and you must have sufficiently indolent disease, so that you can wait it out for the 8 months it could take to make the vaccine. (In contrast, the Favrille vaccine takes only 2 months to make, I am told). If during this waiting period your CLL progresses rapidly for whatever reason, I strongly urge you not to forgo more conventional therapy just because your heart is set on getting the vaccine. We need to fight each battle as it comes, waiting for the vaccine while your CLL gallops ahead is not a smart thing to do. In any case, Prince Charming may not live up to expectations. The vaccine is not likely to be of much use in patients with high tumor load!

The inclusion restrictions of this trial raise an important question. A lucky percentage of CLL patients with good prognostic indicators are Bucket A type smoldering cases (What Type of CLL Do You Have?). Some of these folks would probably never need therapy, or at least not for a long time. Would the Genitope design select a disproportionately large percentage of these guys, because they are the ones who are likely to be in early Rai stages, untreated, and the ones who can afford to wait 8 months without therapy? In other words, would a big chunk of the patients recruited for this trial have done very well anyway, even without the benefits of the Genitope vaccine? The bar may be a bit too low for this trial, in terms of judging the efficacy of the vaccine down the road, because the inclusion criteria may “cherry pick” a particularly easy set of patients.

One way of getting around this complication is to make sure that detailed prognostic information is obtained ahead of time on all the participants in this trial. The real proof of the pudding would be if patients with not-so-good prognostics also have long progression free period after the vaccination. I am waiting to hear if Genitope plans to do such prognostic classification of patients, and if their trial design allows the results to be sliced and diced to distinguish between the results for patients in different risk buckets.

Several years ago I had the privilege of corresponding with Dr. Maurizio Bendandi (Spain), one of the original NCI investigators of B-cell cancer vaccines. He pointed out that making idiotype vaccines for CLL patients is not easy as in the case of NHL patients, and the vaccines may not be as effective either, because CLL patients do not have as many immunoglobulin markers expressed on each cancer cell. While Genitope and Favrille both have demonstrated good success in making idiotype vaccines for NHL patients, this may not be the case for CLL patients. I expect that it may not be possible to make the vaccine at all for a percentage of the CLL patients who volunteer for this trial — and you should be prepared for that disappointment.

Down the road, I hope Genitope will be tempted to expand their technology to include a larger percent of our patient population. For example, it would be nice if vaccines can be used to clean up minimum residual disease (MRD) after more conventional therapies such as Rituxan or its many combinations. Researchers are not fully agreed on what is the best time to administer cancer vaccines. Is it more important to get therapy naïve patients because they are more likely to have undamaged immune systems, or is it more important to have as little tumor load as possible, aim for administering the vaccine after prior de-bulking therapy puts the patient in MRD status, with no more than mere traces of the cancer to fight? Clearly, the second approach will make the technology available to a much larger percent of our patients. As the abstract below suggests, B-cell depletion by Rituxan therapy may not be the kiss of death, as far as vaccination strategy. Dr. Larry Kwak is one of the authors of this paper, and he is also one of the prominent researchers in the area of B-cell cancer vaccines.

Abstract:

Nat Med. 2024 Sep;11(9):986-91. Epub 2024 Aug 21.

Vaccine-induced tumor-specific immunity despite severe B-cell depletion in mantle cell lymphoma.

Neelapu SS, Kwak LW, Kobrin CB, Reynolds CW, Janik JE, Dunleavy K, White T, Harvey L, Pennington R, Stetler-Stevenson M, Jaffe ES, Steinberg SM, Gress R, Hakim F, Wilson WH.

Experimental and Transplantation Immunology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 10 Center Drive, Bethesda, MD.

The role of B cells in T-cell priming is unclear, and the effects of B-cell depletion on immune responses to cancer vaccines are unknown. Although results from some mouse models suggest that B cells may inhibit induction of T cell-dependent immunity by competing with antigen-presenting cells for antigens, skewing T helper response toward a T helper 2 profile and/or inducing T-cell tolerance, results from others suggest that B cells are necessary for priming as well as generation of T-cell memory. We assessed immune responses to a well-characterized idiotype vaccine in individuals with severe B-cell depletion but normal T cells after CD20-specific antibody-based chemotherapy of mantle cell lymphoma in first remission. Humoral antigen- and tumor-specific responses were detectable but delayed, and they correlated with peripheral blood B-cell recovery. In contrast, vigorous CD4(+) and CD8(+) antitumor type I T-cell cytokine responses were induced in most individuals in the absence of circulating B cells. Analysis of relapsing tumors showed no mutations or change in expression of target antigen to explain escape from therapy. These results show that severe B-cell depletion does not impair T-cell priming in humans. Based on these results, it is justifiable to administer vaccines in the setting of B-cell depletion; however, vaccine boosts after B-cell recovery may be necessary for optimal humoral responses.

PMID: 16116429
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Bottom line, I am delighted to see this clinical trial is finally open for patient recruitment. I wish the trial's inclusion criteria were a little broader, so that more patients would be eligible to participate. But I suppose we have to be patient, wait for the next phase trials for that to happen. We did discuss the financial costs of clinical trial participation during the course of our recent conference call with the company. Perhaps something could be worked out in helping needy patients. Last point, I am inclined to think this trial will finish recruitment rather quickly. If you are interested and you fit the inclusion criteria, you should get on the horn to Genitope sooner rather than later. Tell them CLL Topics sent you.