QuoteReplyTopic: Promising vaccines - Discussion Posted: Jan 28 2012 at 11:54am
Hi, Please let me know if I am posting this in the wrong spot but I was reading some articles this morning about cancer in general and found several very promising vaccines mentioned. Here is a link to information about a viral vaccine, jx594 that looks interesting. Apparently, when cancer cells throw off part of their regular cellular composition in order to promote fast growth, they also throw away what protects them against viruses. This vaccine targets that weakness in the cancer cells to induce death in the cancer cell.
I will also go back and see if I can post the original article because there are several such vaccines in progress. This is just one that has some Phase I and Phase II trials open right now. I wanted to see what others in this group think about vaccines such as this one and the one being developed at Roswell Park in NY that currently is recruiting for a Phase I trial.
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Thanks for posting. It looks like most of the trials for JX-594 are in colorectal cancers. Maybe we'll see some more trials opening up on other types of cancers.
They have another one on their site for breast cancer. Here is a link to the one that DOD has apparently been working on- but I believe it requires Her2+1 testing. I found several others, though, that seem to have promising broad application- some that target a protein that is common to many different types of cancer (the JX-594 is one but right now they are focusing on colorectal patients in trials)
I've been very encouraged by what I've been looking at today. I'm laid up from chemo so might as well do some research .
It looks like we might see more research on vaccines. Here's one for Her2+ bc:
4-week vaccination regimen knocks out early breast cancer tumors, Penn researchers report
Researchers at the Perelman School of Medicine at the University of Pennsylvania report that a short course of vaccination with an anti-HER2 dendritic cell vaccine made partly from the patient’s own cells triggers a complete tumor eradication in nearly 20 percent of women with ductal carcinoma in situ (DCIS), an early breast cancer. More than 85 percent of patients appear to have a sustained immune response after vaccination, which may reduce their risk of developing a more invasive cancer in the future. The results of the study were published online this month of Cancer and in the January issue of the Journal of Immunotherapy.
The researchers say the results provide new evidence that therapeutic breast cancer vaccines may be most effective for early, localized disease, and when the treatment goes after a protein critical to cancer cell survival.
Please post any corrections that need to be made to the list above.
If no corrections after a few days, will post list on topic forum: Open Access Links, Articles, TNBC
I just wanted to keep this thread alive because after talking with my oncologist about my upcoming adjuvant chemo treatment, she mentioned that after I'm done with all my treatments, I should keep my eye out on the clinical trials (.gov) website for vaccine therapy in the future. I think if an oncologist is thinking this is a potential avenue for additional treatment, it is worth keeping in mind.
DX IDC TNBC 1/15/12 @ 46; MRI 2.4cm gr3 BRCA2+ 6174delT; LMX 1/31/12 2.5cm, pT2pNO(i)pMX, lymphovascular invasion present; 2/20/12 TAC X 6; 7/2/12 Rad X 25; 9/27/2012 2nd mastectomy & BSO surgery
This does look like a promising area. For patients who have undergone bilateral mastectomy, there should be no residual breast tissue. The strategy for a post adjuvant therapy post mastectomy vaccine could be to make all breast cells immunogenic without attempting to discriminate between normal and cancerous cells. This could be an easier task than targeting tumor cells while leaving normal cells alone. Obviously relevant to TNBC.
Is the TNBC Foundation supporting work in this area?
There is an interim report on the E75 vaccine trial:
Assessment of immunologic response and recurrence patterns among patients with clinical recurrence after vaccination with a preventive HER2/neu peptide vaccine: from US Military Cancer Institute Clinical Trials Group Study I-01 and I-02 http://www.ncbi.nlm.nih.gov/pubmed/18392824
In this report both node positive and node negative patients were analyzed and they all had some degree of Her2 expression (IHC: 1-3+ or FISH >0). In the vaccinated patients who had a recurrence, they tended to have worse prognostic factors (higher nodal status, higher grade tumors, larger tumors, ER/PR-). They recurred despite having the same immune response as the vaccinated cohort that did not recur. The hypothesis is that the immune response eliminated lower grade tumors while allowing the more aggressive tumors to emerge. However, the survival of the vaccinated recurrent patients was better than the non-vaccinated patients who recurred : 1/8 patients vs 5/12 patients. Note the patient numbers are very small. Phase 3 is ongoing.
There is an interim report on the E75 vaccine trial: Accordingly, the survival of the vaccinated recurrent patients was worse than the non-vaccinated patients who recurred (41.7% and 12.5%). Note the patient numbers are very small. Phase 3 is ongoing.
Lee,
The interim results seem disturbing to me as it looks like the vaccinated recurrent patients did much worse, especially with higher grade tumors like TNBC. Thanks for posting the interim report.
Donna
DX IDC TNBC 6/09 age 49, Stage 1,Grade 3, 1.5cm,0/5Nodes,KI-67 48%,BRCA-,6/09bi-mx, recon, T/C X4(9/09) 11/10 Recur IM node, Gem,Carb,Iniparib 12/10,MRI NED 2/11,IMRT Radsx40,CT NED11/13,MRI NED3/15
Donna See amended post. There was a discrepancy between the text of the paper and the figure on mortality rate: Quoting the text: "Among recurrent patients, the V-R and C-R groups mortality rate was 41.7 (5/12) and 12.5%
(1/8), respectively (P = 0.3) (Fig. 8).
"
Fig. 8 Recurrence and survival rates for all patients completing the trial (n = 177). The control and vaccinated groups had recurrence rates of 14.8 and 8.3%, respectively (P = 0.17) and mortality rates of 6.2 and 1.0%, respectively (P = 0.1). In the recurrent patients, the mortality rate for the control and vaccinated groups were 41.7 and 12.5%, respectively;
P = 0.3)
VR: vaccinated patients who recurred. CR: control patients who recurred.
The editor or reviewer should have picked up on the discrepancy.
Thanks for letting me take a second look and correcting the mistake.
You are a one woman pubmed search engine. I can't keep up. Let me know if you'd be interested in my sending you some article links to your PM to embed in your posts, simply to consolidate for other readers. There are a lot of recent articles that have come out in Cancer Cell in the past few months that may be of interest.
DX IDC TNBC 1/15/12 @ 46; MRI 2.4cm gr3 BRCA2+ 6174delT; LMX 1/31/12 2.5cm, pT2pNO(i)pMX, lymphovascular invasion present; 2/20/12 TAC X 6; 7/2/12 Rad X 25; 9/27/2012 2nd mastectomy & BSO surgery
Immune Response Markers for Cancer Vaccines Paint a Clearer Picture
In trying to understand what constitutes an effective immune response, researchers find it’s all about T cells.
Patricia F. Dimond, Ph.D.
A key hurdle in the development of
cancer immunotherapies has been the absence of biomarkers that indicate
the efficacy and kinetics of antitumor immune responses. The
identification of immune response biomarkers may also predict which
patients are most likely to benefit from active immunotherapies.
As data accumulates, a clearer picture of the immune correlates for
an effective anti-tumor response is emerging. Cancer immunotherapy
involves stimulation of the immune system with reagents such as
vaccines, T cells, or cytokines. These agents stimulate antitumor
response either by increasing effector cell numbers or by producing one
or more soluble mediators such as lymphokines. They may also act to
decrease suppressor mechanisms, causing tumor cells to increase their
immunogenicity and making them more susceptible to immunologic defenses.
To date, FDA has approved one autologous therapeutic cancer vaccine
for certain men with metastatic prostate cancer, Dendreon’s Provenge
(sipuleucel-T). The vaccine consists of autologous peripheral blood
mononuclear cells (PBMCs) including antigen presenting cells (APCs) that
have been activated ex vivo with a recombinant fusion protein, PA2024.
The fusion protein consists of prostatic acid phosphatase (PAP) and
granulocyte-macrophage colony-stimulating factor (GMCSF).
Dendreon
Dendreon presented data at the
American Society of Clinical Oncology’s “2012 Genitourinary Cancers
Symposium” this February on clinical results and mechanism of action
studies among prostate cancer patients treated with Provenge. The
company reported Phase II data from its NeoACT study, undertaken to
provide understanding of Provenge’s immunologic effects.
The open-label trial included 42 patients and analyzed immune
responses to sipuleucel-T among patients with localized prostate cancer.
Patients received three infusions of Provenge at approximately two-week
intervals beginning 6–7 weeks prior to radical prostatectomy (RP)
surgery.
The researchers concluded that “neoadjuvant sipuleucel-T resulted in
robust immune system activation that included antigen presenting cells,
memory and activated mature B cells, and both CD4+ and CD8+ T cells. The
patterns observed at the second and third infusions, relative to the
first, are consistent with an immunological prime-boost profile.”
The company also reported immune responses in prostate tumor tissue
following neoadjuvant sipuleucel-T in patients with localized prostate
cancer. In this study, immunohistochemical (IHC) analysis showed that
sipuleucel-T treatment resulted in an increased frequency of T cells in
prostate cancer tissue at the rim between the benign and malignant
glands. The data suggests that sipuleucel-T may modulate the presence of
lymphocytes at the prostate tumor site. The company and others
commenting on this and other immune response data say that “Provenge
should be studied in earlier stages of disease, when patients have less
tumor burden.”
Abramson Cancer Center
Researchers at the Perelman School of
Medicine and the Abramson Cancer Center at the University of
Pennsylvania reported last month that a short course of vaccination with
an anti-Her2 dendritic cell vaccine made partly from the patient’s own
cells triggered complete tumor eradication in nearly 20% of women with
ductal carcinoma in situ (DCIS). Brian Czerniecki, M.D., Ph.D.,
surgical director of the immunotherapy program for the Abramson Cancer
Center, enrolled 27 women with Her2-positive DCIS in the vaccine study.
The investigators isolated lymphocytes from patients’ blood, then
activated dendritic cells, priming them with small segments of the
Her2/neu protein. Each patient then received four injections one week
apart. After two weeks patients had surgery to remove any remaining
disease, the standard of care for DCIS patients.
At surgery, 5 of 27 (18.5%) vaccinated subjects had no evidence of
remaining disease. In the 22 subjects with residual DCIS, Her2/neu
expression was eradicated in 11 (50%) of them, and reduced by 20 percent
or more in another two. “We are continuing to see this pattern in our
second, ongoing trial,” Dr. Czerniecki says. When comparing estrogen
receptor (ER) negative with ER-positie DCIS lesions, vaccination was
more effective in hormone-independent DCIS. After vaccination, no
residual DCIS was found in 40% of ER-negative subjects compared with
5.9% in ER-positive patients.
In analyzing patient immune responses, the investigators found that
85% had Her2-reactive CD4 and CD8 T cells. This suggests that the
patients developed a robust and relatively complete immune response
after vaccination. Some patients maintained their immune responses for
as long as 52 months.
“Previous vaccines targeted tissue antigens that were expressed on
the cancer cells but were not necessary for tumor survival,” Dr.
Czerniecki noted. “So a vaccine response would cause the tumor to just
stop expressing the antigen and the tumor would be fine. Here we’re
going after Her2/neu, which is critical for survival of early breast
cancers. If we knock it out with the immune response, we cripple the
tumor cells.”
Regarding Herceptin, Dr. Czerniecki told GEN, “Herceptin is an
anti-Her2/neu antibody. This autologous vaccine activates anti-Her2 CD4,
CD8, and antibodies.” Because of the nature of the vaccine, patients’
immune responses are maintained against Her2. “Herceptin lasts few
months and is gone; it is only antibody therapy,” Dr. Czerniecki
explained.
“Eventually if we get this working a little better with some
combinations such as vaccine plus trastuzumab or lapatinib, this could
be a standalone therapy alternative, allowing the immune response to
last longer,” Dr. Czerniecki added. “Ultimately the goal is to prevent
disease recurrence and avoid radiation therapy.”
Biovest
Last December Biovest International
presented results of an 11-year, Phase II study it conducted with NCI
testing its BiovaxID® in the treatment of mantle cell lymphoma (MCL).
Study results showed that BiovaxID active immunotherapy following
treatment with rituximab combination chemotherapy induced nearly
universal immune responses. These responses, which strongly correlated
with overall survival (OS) in treated patients, primarily consisted of
tumor-specific T-cell immune responses.
BiovaxID comprises a protein isolated from each patient’s tumor
combined with a carrier protein and administered with GMCSF. It
stimulates the immune system to target a protein (idiotype) exclusively
expressed on malignant B cells.
As part of the clinical development of BiovaxID, in 2000 the NCI
began the Phase II trial in MCL patients who received
rituximab-combination chemotherapy (etoposide, vincristine, doxorubicin,
cyclophosphamide, prednisone, rituximab; EPOCH-R) prior to vaccination
with BiovaxID to determine the impact of severe B-cell depletion on
vaccine-induced immune responses.
With 122 months of median follow-up, the median overall patient
survival in this study was 104 months. The investigators reported a
significant association between T-cell immune responses (measured by
antitumor, post-vaccine T-cell cytokine induction) and overall survival.
The median overall survival in patients who did not develop or
developed a below-median vaccine-induced T-cell response was 79 months
at the time of follow-up.
“Our clinical trial experience with BiovaxID immunotherapy
demonstrates that vaccination of lymphoma patients results in a broad
spectrum antitumor immune response involving both cellular and humoral
immune repertoires,” Carlos Santos, Ph.D., Biovest’s svp told GEN.
“Further, randomized clinical trial data demonstrate that vaccination
effectively extends remission duration lymphoma.
Dr. Santos emphasized that Biovest’s 11-year follow up with these
vaccines “now shows that not only does vaccination provide clear
improvements in remission duration but also that these vaccines may
fundamentally alter tumor kinetics over many years. T-cell immune
responses primed by Id vaccination in turn change tumor growth such that
patients survive with lower disease aggressiveness.”
Moreover, he said, clinicians now for the first time may offer
patients therapies that may truly add benefit without also adding
significant risk, changing the risk/benefit equation in cancer treatment
in ways even a decade ago would have seemed far beyond reach.
Patricia F. Dimond, Ph.D. (drpdimond@comcast.net), is a principal at BioInsight Consulting.
Hopefully we'll see TNBC specific vaccines in development soon -- however that still requires knowing what binds all the TNBCs together, not just the fact TNBC lacks 3 receptors.
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