Tumor Immunotherapy in Cancer : A Novel Approach

Dear vishal,
Antibodies are useful tools for the immune system to combat pathogens, but also for the biology research scientist to conduct a variety of experiments which can probe ever further into the mysteries of life.
Monoclonal antibodies are produced by hybridomas and are exact in their target epitope binding.However, more than a quarter century after their introduction, monoclonal antibodies are still produced only by somatic cell clones of splenocytes fused to multiple myeloma-derived cells (hybridomas).The process of hybridoma production is rarely completed in two months and often takes well over one year.
olyclonal antibodies are useful for detecting proteins which have lower expression levels as more antibodies can bind a single protein molecule, thus enhancing the detection signal. Polyclonals generated against full-length recombinant protein targets are specifically recommended for immunoprecipitations and other techniques involving native protein conformation. When conducting an immunoprecipitation, maximized antibody binding is necessary to ensure pull-down of the target and any potential binding partners, in spite of the regions of the target protein which may be blocked by those binding partners.
Peptide polyclonal antibodies are produced following immunization to a peptide carefully selected from the target sequence. Because these polyclonal antibodies recognize only a particular portion of the target protein, in an unfolded state, these antibodies are recommended for Western blots and immunofluorescent and immunohistochemical staining.
The internal image antibody is the other form specific for a biological receptor, but does not require isolation of the receptor to prepare the antibody, and provides the desired specificity and selectivity for targeted diagnosis or therapy.
It is produced by the following way:
a) selecting a ligand that binds to a desired receptor;(b) preparing a first generation of monoclonal antibodies against the receptor binding ligand;(c) isolating the first generation of monoclonal antibodies;(d) preparing monoclonal anti-idiotypic antibodies against the first generation of monoclonal antibodies to result in internal image anti-receptor antibodies;(e) isolating the internal image anti-receptor antibodies;(f) conjugating the internal image anti-receptor antibodies to a photoactive dye;(g) administering a concentration of the conjugate of step f to a patient effective to diagnose the patient;(h) allowing the conjugate to accumulate at a target site within the patient; and(i) exposing the target site to light sufficient to activate the photoactive dye to image the target site.

2.These Ab produced are highly antigen specific and they may not be effective for the mutant versions of the same tumors.

References:
1.Janeway, C.A., et al. Immunobiology.(2001) Garland Science.
2.Waldmann, T.A. Immunotherapy: past, present and future. (2003) Nat. Med. 9: 269-277.
3.Coligan, J.E., et al. Current Protocols in Immunology. (2002) John Wiley & Sons, Inc.
4.http://www.wipo.int
5.http://www.faqs.org/patents/app/20090016965

Dear Sir,
An article in the conservative Journal of the National Cancer Institute suggests that cancer is actually a self-limiting disease. It has been observed in many types of tumors that they grow steadily to full size, and then disappear. This also applies to leukemia.
So its like may be because of healthy diet which can enhance the immunity of the patient overcoming the cancer growth.also because of the lack of suitable environment in and around the tumor cells,they may shed their growth.
Reference:
http://www.health-science-spirit.com/cancerintroduction.html

Dear Sir,
An article in the conservative Journal of the National Cancer Institute suggests that cancer is actually a self-limiting disease. It has been observed in many types of tumors that they grow steadily to full size, and then disappear. This also applies to leukemia.
So its like may be because of healthy diet which can enhance the immunity of the patient overcoming the cancer growth.also because of the lack of suitable environment in and around the tumor cells,they may shed their growth.

Dear Komal Madam,
Here are your answers:
Some of the Enzymatic tumor markers:
Aspartate Transaminase for liver cancer.
Alkaline phosphatase:Bone cancer
Acid Phosphatase:Prostate Cancer.
Lactate dehydrogenase:Leukemia also
Galactosyl Transferase II:variety of malignancies, predominantly gastrointestinal
hormonal tumor markers:
Human Chorionic Gonadotropin: All gestational trophoblastic tumors produce it.
Brain tumor Markers:
Endosialin (tumor endothelial marker 1, TEM1):
abundantly expressed in highly malignant and invasive brain tumors.
PGD-S (Prostaglandin D synthetase):
a 30 kDa glycoprotein also known as beta-trace protein that catalyzes the formation of prostaglandin D2 (PGD2) from PGH2, is a potentially useful marker for brain tumor.
PV-1 (Plasmalemmal vesicle associated protein-1)
represents a novel marker of brain tumor angiogenesis and integrity of the blood-brain barrier and is a potential therapeutic target.
Neuron Specific Enolase:
Neuron specific enolase is an isozyme of the glycolytic pathway that is found only in brain and neuroendocrine tissue.
References:
1.Dr.U.Satyanarayas,Biochemistry,Nucleic acids.2 edition,2002.pp105-106.
2.http://www.tc-cancer.com
3.Flaschka G, Marth E, Desoye G, Freidl W, Walzl M,Diagnostic value of biochemical tumor markers in brain tumors. Review of the literature and own experience with serum analysis of sialic acid (NANA), carcinoembryonic antigen (CEA) and neuron-specific enolase.Zentralbl Neurochir. 1990;51(3):129-37.

Dear Amit,
The immune system boosters are potential adjuvants which enhances the tumor antigenicity and the effectiveness of the primary therapy used by act through one of the several mechanisms:
1) by altering tumor cells to increase their immunogenicity and make them more susceptible to immunologic defenses;
2) by stimulating the antitumor response, either by increasing the number of effector cells or by producing one or more soluble mediators such as lymphokines; 3) by decreasing immune suppressor mechanisms; and
4) by improving tolerance to cytotoxic drugs or radiotherapy, such as stimulating bone marrow function with granulocyte colony-stimulating factor (G-CSF)
Reference:
1.Kirkwood JM, Strawderman MH, Ernstoff MS, Smith TJ, Borden EC, Blum RH. Interferon alfa-2b adjuvant therapy of high-risk resected cutaneous melanoma: the Eastern Cooperative Oncology Group Trial EST 1684. J Clin Oncol. 1996;14:7-17.
2.Eggermont AM. The current EORTC Melanoma Cooperative Group adjuvant trial programme on malignant melanoma: prognosis versus efficacy, toxicity, and costs. Melanoma Res. 1997;7:S127-S131.

Dear Amit,
The immune system boosters are potential adjuvants which enhances the tumor antigenicity and the effectiveness of the primary therapy used by act through one of the several mechanisms:
1) by altering tumor cells to increase their immunogenicity and make them more susceptible to immunologic defenses;
2) by stimulating the antitumor response, either by increasing the number of effector cells or by producing one or more soluble mediators such as lymphokines; 3) by decreasing immune suppressor mechanisms; and
4) by improving tolerance to cytotoxic drugs or radiotherapy, such as stimulating bone marrow function with granulocyte colony-stimulating factor (G-CSF)

Dear Pankaj,
1.The biggest challenges in cancer therapy are:
For Chemotherapy:lack of specificity and severe toxicity.
Radiotherapy: They themselves are carcinogenic if given in excess doses.
Immunotherapy:The targets are different among different patients, and the targets change when cancer cells mutate.
2.Yes,our immune system is able to detect tumor cells which produce antigenic markers on their surface.but as the disease progresses and because of the mutations they secrete certain factors (like Macrophage inhibitory factors)which will evade the immune attack.
references:
1.http://www.cel-sci.com
2.Pardoll, D. Does the immune system see tumors as foreign or self? AnnuRev Immunol. 2003. 21:807-39.

Here are your answers:
1.polyclonal antibodies have the capability of detecting a multiplicity of epitopes and therefore recognise antigen from different orientations.This property is important in certain assays where the detection of an analyte would be compromised by the use of a single epitope. In addition, polyclonal reagents are relatively simple and cheap to produce in the short term compared with monoclonal reagents.
Inspite of these advantages they are limited in their usage when compared with monoclonal antibodies because polyclonal Ab's in general suffer from a lack of reproducibility.In contrast, the continuous culture of B cell hybridomas(MAB's) offers a reproducible and potentially inexhaustible supply of antibody with exquisite specificity.
Vaccines themselves uses the administration of Ab's.But the active immunization is far more effective than the passively administered Ab's.

2.Targeted therapies may cause flu-like symptoms including fever, chills,fluid retention, nausea, vomiting, appetite loss, fatigue and even blood pressure may also be affected.
The following instructions have to be followed:
a.Take the medication with a full glass of water to allow the drug to disperse throughout the system. Being properly hydrated may also prevent fluid retention around the face and eyes.
b. taking medication on a full stomach may lessen certain side effects, such as nausea and diarrhea.
c.These therapies, like any other medication affecting the immune system, can cause adverse effects that may prove life threatening. For example, severe hypersensitivity (allergic) reactions to specific ingredients.However, such severe reactions are quite rare.Certain prescription medications may be able to combat or lessen more serious side effects.
References:
1.P N Nelson,G M Reynolds,E E Waldron,E Ward,K Giannopoulos, and P G Murray,Monoclonal antibodies,Mol Pathol. 2000; 53(3): 111–117.
2.http://cancernet.nci.nih.gov/cancertopics/factsheet/Therapy/biological
3.http://www.ehow.com/how_2033748_lessen-side-effects.html
4.Francisco J. Esteva,Monoclonal Antibodies, Small Molecules, and Vaccines in the Treatment of Breast Cancer.The Oncologist,2004,9 (3):4–9.

Dear Hemangi,
Cancer vaccines are a unique approach to cancer therapy. They exert an antitumor effect by engaging the host immune response, and have great potential for circumventing the intrinsic drug resistance that limits standard cancer management. Additional advantages of cancer vaccines are exquisite specificity, low toxicity, and the potential for a durable treatment effect due to immunologic memory.Vaccines to prevent infectious diseases are prophylactic (or preventive). In contrast most cancer vaccines are expected to be therapeutic (destroying a tumor that has already developed). The exceptions are vaccines to prevent cancers induced by infectious agents, such as Human papilloma virus (HPV) that causes cervical cancers and Helicobacter pylori bacteria believed to cause gastric cancers. HPV16 and HPV18 together account for 70% of cervical cancers, and a vaccine recently developed against these two strains shows great promise.
Available Cancer Vaccines:
Gardasil and Cervarix for Cervical Cancers and Canvaxin,Melacine are effective against melanomas.
Inspite of their effectives still we have increasing cancer rates because it has some limitations.Many cancers are not caused by infectious agents. For these, designing cancer vaccines offers more challenges than vaccines against infectious agents.One challenge is that most tumor antigens are self antigens. So it is hard to induce long-term immunological memory against tumor antigens without producing autoimmunity. Overcoming immunosuppression is another factor.

While the development of cancer vaccines has been challenging and more complex than anticipated, its future appears to be promising. It should soon be possible to develop vaccines to prevent the occurrence of cancers caused by infectious agents (HPV-induced cervical cancer and Helicobacter-induced gastric cancer).
References;
Morse M.A., Clay TM Lyerly HK "Biology of the Cancer Vaccine Immune Response" Handbook of Cancer Vaccines (2004) 3-17.
Yu Z., Restifo "Cancer Vaccines: Progress Reveals New Complexities" J. Clin. Invest (2002) 110:289-294.
Robbins P.F., "Tumor Antigen Discovery with T Cells" Handbook of Cancer Vaccines (2004):31-47

Mr.Suhaas,
Here are your answers:
1.Yes, it is possible to arrest the growth of cancer cells irrespective of their mode of origin provided if they express some antigenicity.
Ref:
S. Ben-Efraim,Cancer immunotherapy: potential involvement of mediators.Mediators Inflamm. 1997,6(3): 163–173.

2.The following are the antibodies used:
Alemtuzumab (Campath®) against CD52 protein in CLL.
Herceptin® against HER2 Protein in breast cancer.
Bevacizumab against VEGF( VAscular Epithelial Growth Factor)
Gemtuzumab ozogamicin (Mylotarg®) against CD33 proteins in Leukemia.
Rituximab (Rituxan® or Mabthera®) against the CD20 antigen in Non Hodgkins disease.
Ref:
http://www.cancerquest.org

3.Immunization against a particular cancer is not effective against malignancies likely to occur in other tissues and organs.this is because there is a heterogenous expression of surface antigens by the tumor cells which facilitates the evasion from Immune attack.
ref:
P. A. Edwards,Heterogeneous expression of cell-surface antigens in normal epithelia and their tumours, revealed by monoclonal antibodies.Br J Cancer. 1985, 51(2): 149–160.

Dear Sirisha,
heres ur answer:
Interferons are used to treat several different types of cancer, particularly renal cell (kidney) cancer, malignant melanoma, multiple myeloma and some types of leukaemia. It is also used to treat diseases other than cancer.
Interferon-alfa2b is approved for use after surgery in patients with malignant melanoma who are free of the disease but are at a high risk for recurrence.
Reference:
http://www.cancerhelp.org.uk
http://skincancer.about.com.

and for tumor immunotherapy classification please go through the slides.

Iam thankful for your queries.The answers are as follows:

1.Large quantitative differences in antigen expression exist between tumor cells.The antigens are, in general, expressed independently of one another.This heterogeneity in antigen expression may be related to different expressions in the various phases of the cell cycle.
Reference:
Silvia Fargion, Desmond Carney et a.,Heterogeneity of Cell Surface Antigen Expression of Human Small Cell Lung Cancer Detected by Monoclonal Antibodies.1986,CANCER RESEARCH 46:2633-2638.

2.The following techniques are adopted for identification of surface antigens:
Laser capture microdissection (LCM):Isolation of cells from tissue section on
slide using laser excision.
Fluorescence in situ hybridization (FISH):Detection of specific gene in cell
nuclei using fluorescence-labeled
cDNA as probe.
Chromogenic in situ hybridization (CISH):Detection of gene amplification using
chromogenic-based method.
Cancer profiling array (CPA):RNA from different tumor types and matching normal
spotted onto membrane.
Quantitative real time PCR :Real-time method for detecting and quantifying
nucleic acids.
Multi-dimensional liquid chromotography/mass spectrometry1 Isotope-coded affinity tag :Proteins are profiled using a stable isotope tagging (1H, 2H)
Immunohistochemistry (IHC):In situ detection of proteins in tissues using
antibody coupled to a chromogenic enzyme.
Tissue microarrays (TMA):Tissue cores from different donor blocks assembled in
array format and simultaneously analyzed by in situ
methods.etc.,
Reference:
Paul Carter, Leia Smith and Maureen Ryan,Identification and validation of cell surface antigens for antibody targeting in oncology.Endocrine-Related Cancer 11 (4) 659 -687.

3.A dendrimer is generally described as a macromolecule, which is characterized by its highly branched 3D structure that provides a high degree of surface functionality and versatility.Dendrimers are built from a starting atom, such as nitrogen, to which carbon and other elements are added by a repeating series of chemical reactions that produce a spherical branching structure. As the process repeats, successive layers are added, and the sphere can be expanded to the size required by the investigator. The result is a spherical macromolecular structure whose size is similar to albumin and hemoglobin, but smaller than such multimers.It is the hyperbranching when going from the centre of the dendrimer towards the periphery, resulting in homostructural layers between the focal points (branching points). The number of focal points when going from the core towards the dendrimer surface is the generation number.The core part of the dendrimer is sometimes denoted generation “zero”, or in the terminology presented here “G0”. The core structure thus presents no focal points, as hydrogen substituents are not considered focal points. Intermediates during the dendrimer synthesis are sometimes denoted half-generations.

4.Almost all types of carcinomas can be treated using Immunotherapy.
The FDA has approved several cancer immunotherapies, including Bacille Calmette-Guérin (BCG), interferon-alfa (IFN-alfa), interleukin-2 (IL-2), and the monoclonal antibodies.
Few examples:
Melanoma is probably the most-studied cancer when it comes to immunotherapy because other treatments, like chemotherapy, don't work as well against this cancer as they do for most cancers.The cytokines IFN-alfa and IL-2 are approved to treat people with metastatic melanoma and advanced kidney cancer.
Interferon-alfa can be used to treat people with hairy cell leukemia, chronic myelogenous leukemia, follicular lymphoma, multiple myeloma, and cutaneous (skin) T cell lymphoma.
Denileukin diftitox, a combination of IL-2 and diphtheria toxin, is sometimes used to treat cutaneous T cell lymphoma.
Rituximab (Rituxan), a monoclonal antibody (MAb), is used to treat some kinds of B cell non-Hodgkin lymphoma.
Two vaccines (Gardasil® and Cervarix®) are highly effective against cervical cancers.
Bevacizumab and Cetuximab are used against advanced colorectal cancer.
Reference:
http://www.cancer.org.

Hi Amol here is your answer:
The following cancer screening guidelines are recommended for early diagnosis for those who are at average risk for cancer and without any specific symptoms:
Breast cancer:
Clinical breast exam (CBE) should be part of a periodic health exam, about every 3 years for women in their 20s and 30s and every year for women 40 and over.
Breast self-exam (BSE) is an option for women starting in their 20s.
Women at high risk (greater than 20% lifetime risk) should get an MRI and a mammogram every year.
Colon and rectal cancer:
Tests that find polyps and cancer

1.flexible sigmoidoscopy every 5 years
2.colonoscopy every 10 years
3.double contrast barium enema every 5 years
4.CT colonography (virtual colonoscopy) every 5 years

Tests that mainly find cancer

1.fecal occult blood test (FOBT) every year
2.fecal immunochemical test (FIT) every year
3.stool DNA test (sDNA)

Cervical cancer:
Women should begin cervical cancer screening when they are about 21 years old. Screening should be done every year with the regular Pap test or every 2 years using the newer liquid-based Pap test and the HPV DNA test.

Endometrial (uterine) cancer:
Women with or at high risk for hereditary non-polyposis colon cancer (HNPCC), annual screening should be offered for endometrial cancer with endometrial biopsy.

Prostate cancer:
testing for the prostate-specific antigen (PSA) blood test and digital rectal exam (DRE) yearly are highly recommended.

References:

American Cancer Society. Cancer Facts & Figures 2009. Atlanta, Ga: American Cancer Society; 2009.

Levin B, Lieberman DA, McFarland, et al. Screening and Surveillance for the Early Detection of Colorectal Cancer and Adenomatous Polyps, 2008: A Joint Guideline from the American Cancer Society, the US Multi-Society Task Force on Colorectal Cancer, and the American College of Radiology. Published online March 5, 2008. CA Cancer J Clin. 2008;58.

Recent development:
The researchers have shown for the first time that nanoscale changes are present in cells extremely early on in carcinogenesis. Using partial-wave spectroscopy (PWS),it is possible to detect subtle abnormal changes in human cancer cells (Colon) even when those same cells appear normal using conventional microscopy.
Reference:
The study is published online by the Proceedings of the National Academy of Sciences.

Dear Sir,
A cancerous growth or neoplasm is clonal. That is, all its cells are descendants of a single cell(Monoclonal)which have escaped the control of the forces regulating cellular growth.
Reference Cited:
http://www.history.com/encyclopedia.do?articleId=204505.

Dear Shobhadeepthi,
I appreciate your zest for the topic.
And here are your answers.
1.Cytotoxic drug incorporation into liposomes has been reported since the mid-1970s. These early reports laid the groundwork for selecting therapeutic agents amenable to incorporation by liposomes, as well as determining optimal liposome size and net charge required for effective drug delivery.Later studies refined many of the considerations required for effective liposome-mediated drug delivery. Today, drugs of various chemical properties have been successfully packaged, including hydrophilic drugs such as N-(phosphonoacetyl)-L-aspartate, hydrophobic drugs such as paclitaxel, and amphipathic drugs such as doxorubicin.One effective means of targeting tumors would be via conjugation of antitumor antibodies or portions of antibodies to liposomes (immunoliposomes). In this approach, it has become apparent that many factors must be taken into consideration, including proper choice of target antigen, antibody function, and antibody-liposome linkage.Thus, tumor antigens must be identified, and the biological response of a given antibody toward the tumor antigen determined.Despite the potential difficulties, the successful use of mAbs such as herceptin in immunotherapy suggests that immunoliposomes may represent a viable approach. In addition, cellular internalization of antibodies increases efficacy of drug delivery, presumably by inducing tumor cells to endocytose immunoliposomes. This is the case with the HER2-targeted immunoliposomes, which distribute within solid tumors and not simply in the extracellular space surrounding the tumor blood vessels.As the use of immunoliposomes as anticancer agents approaches in clinical trials, more questions arise like What would be the immediate and long-term effects of immunoliposome administration in patients? Will immunoliposomes, similar to mAbs, also be able to overcome potential barriers such as tumor heterogeneity? Will immunoliposomes be effective in combination therapies? These and other questions await further studies.
Referenced from: Drummond D. C., Meyer O., Hong K., Kirpotin D. B., Papahadjopoulos D. Optimizing liposomes for delivery of chemotherapeutic agents to solid tumors. Pharmacol. Rev., 51: 691-743, 1999.

Park J. W., Hong K., Kirpotin D. B., Papahadjopoulos D., Benz C. C. Immunoliposomes for cancer treatment. Adv. Pharmacol., 40: 399-435, 1997.

2.Although there are more malignancies associated with AIDS,the commonest are KAPOSI'S Sarcoma and Lymphoma.Indeed treatment per se with antiretroviral therapy results in improvement of (In some cases complete resolution )Kaposis sarcoma.when the condition is troublesome local radiotherapy or intralesional chemotherapy(Vincristine) can be beneficial.
In the cases of other solid tumors combination of Vincristine + Bleomycin has been considered as the first line regimen.The liposomal formulations of Doxorubicin and Daunorubicin are more effective.Etoposide has also been tried orally or Intravenously in in recalcitrant cases.
lastly encouraging results are seen with Paclitaxel.
Lymphomas are treated using CHOP regimen(Cyclophosphamide,Doxorubicin,Oncovin and Prednisolone)
Reference: Leake DH,Fisher M.HIV Infection,Roger Walker's,Clinical Pharmacy and Therapeutics.III edition.pp614-617.

3.Some Novel drug Carriers in Cancer:
a.Multifunctional magnetic polycation drug carriers (MPDCs) are synthesized to provide simultaneous magnetically targeted cancer therapy.
b.Cyclodextrin-covered gold nanoparticles for targeted delivery.
c.polymer drug conjugates.Eg: N-(2-hydroxypropyl)methacrylamide copolymer(HPMA)+ Doxorubicin is in Phase II trials.
References in the order:

Sung-Baek Seo,Jaemoon Yang et al,Novel multifunctional PHDCA/PEI nano-drug carriers for simultaneous magnetically targeted cancer therapy and diagnosis via magnetic resonance imaging.Nanotechnology.

Chiyoung Park et al,Cyclodextrin-covered gold nanoparticles for targeted delivery of an anti-cancer drug.J. Mater. Chem., 2009, 19, 2310-2315.

R Duncan,Polymer–drug conjugates: towards a novel approach for the treatment of endrocine-related cancer.Endocrine-Related Cancer 12 (Supplement_1) S189 -199.

4.The following are the drugs in trials against cancer:
Drug: EPC2407 (crinobulin)
A Anti-Cancer Drug With Vascular Disrupting Activity: In Patients With Advanced Cancer
Drug: Ciclopirox
Chemoprevention of Cancer in the Lower Female Genital Tract: The Antineoplastic Activity of the Fungicide Ciclopirox.
Drug: MK6592
Treatment With MK6592 an Anti-Cancer Drug in Patients With Advanced Solid Tumors.
The list is elaborative.you can find more on the following link.

Reference: http://clinicaltrials.gov/ct2/results?term=cancer+drugs .

Hope I answered all your doubts.thanks for motivating me.